Piperazine derivatives useful as CCR5 antagonists

ABSTRACT

The use of CCR5 antagonists of the formula  
                 
or a pharmaceutically acceptable salt thereof, wherein R is optionally substituted phenyl, pyridyl, thiophenyl or naphthyl; 
         R 1  is hydrogen or alkyl;    R 2  is substituted phenyl, substituted heteroaryl, naphthyl, fluorenyl, diphenylmethyl or optionally substituted phenyl- or heteroaryl-alkyl;    R 3  is hydrogen, alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, or optionally substituted phenyl, phenylalkyl, naphthyl, naphthylalkyl, heteroaryl or heteroarylalkyl;    R 4 , R 5  and R 7  are hydrogen or alkyl;    R 6  is hydrogen, alkyl or alkenyl; for the treatment of HIV, solid organ transplant rejection, graft v. host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, allergies or multiple sclerosis is disclosed, as well as novel compounds, pharmaceutical compositions comprising them, and the combination of CCR5 antagonists of the invention in combination with antiviral agents useful in the treatment of HIV or agents useful in the treatment of inflammatory diseases.

This application is a continuation-in-part (CIP) of U.S. Ser. No.10/668,862 filed Sep. 23, 2003, which is a divisional of of U.S. Ser.No. 10/061,011, filed Jan. 30, 2002, now U.S. Pat. No. 6,689,765 B2,which is a divisional of U.S. Ser. No. 09/562,814, filed May 1, 2000,now U.S. Pat. No. 6,391,865 B1, which claims the benefit of U.S.Provisional Application No. 60/132,509, filed May 4, 1999. Each of theabove-mentioned application is incorporated herein in its entirety byreference.

BACKGROUND

The present invention relates to piperazine derivatives useful asselective CCR5 antagonists, pharmaceutical compositions containing thecompounds, and methods of treatment using the compounds. The inventionalso relates to the use of a combination of a CCR5 antagonist of thisinvention and one or more antiviral or other agents useful in thetreatment of Human Immunodeficiency Virus (HIV). The invention furtherrelates to the use of a CCR-5 antagonist of this invention, alone or incombination with another agent, in the treatment of solid organtransplant rejection, graft v. host disease, arthritis, rheumatoidarthritis, inflammatory bowel disease, atopic dermatitis, psoriasis,asthma, allergies or multiple sclerosis.

The global health crisis caused by HIV, the causative agent of AcquiredImmunodeficiency Syndrome (AIDS), is unquestioned, and while recentadvances in drug therapies have been successful in slowing theprogression of AIDS, there is still a need to find a safer, moreefficient, less expensive way to control the virus.

It has been reported that the CCR5 gene plays a role in resistance toHIV infection. HIV infection begins by attachment of the virus to atarget cell membrane through interaction with the cellular receptor CD4and a secondary chemokine co-receptor molecule, and proceeds byreplication and dissemination of infected cells through the blood andother tissue. There are various chemokine receptors, but formacrophage-tropic HIV, believed to be the key pathogenic strain thatreplicates in vivo in the early stages of infection, the principalchemokine receptor required for the entry of HIV into the cell is CCR5.Therefore, interfering with the interaction between the viral receptorCCR5 and HIV can block HIV entry into the cell. The present inventionrelates to small molecules which are CCR5 antagonists.

CCR-5 receptors have been reported to mediate cell transfer ininflammatory diseases such as arthritis, rheumatoid arthritis, atopicdermatitis, psoriasis, asthma and allergies, and inhibitors of suchreceptors are expected to be useful in the treatment of such diseases,and in the treatment of other inflammatory diseases or conditions suchas inflammatory bowel disease, multiple sclerosis, solid organtransplant rejection and graft v. host disease.

Related piperazine derivatives which are muscarinic antagonists usefulin the treatment of cognitive disorders such as Alzheimer's disease aredisclosed in U.S. Pat. Nos. 5,883,096; 6,037,352; 5,889,006.

A-M. Vandamme et al., Antiviral Chemistry & Chemotherapy, 9:187-203(1998) disclose current clinical treatments of HIV-1 infections in manincluding at least triple drug combinations or so-called Highly ActiveAntiretroviral Therapy (“HAART”); HAART involves various combinations ofnucleoside reverse transcriptase inhibitors (“NRTI”), non-nucleosidereverse transcriptase inhibitors (“NNRTI”) and HIV protease inhibitors(“PI”). In compliant drug-naive patients, HAART is effective in reducingmortality and progression of HIV-1 to AIDS. However, these multidrugtherapies do not eliminate HIV-1 and long-term treatment usually resultsin multidrug resistance. Development of new drug therapies to providebetter HIV-1 treatment remains a priority.

SUMMARY OF THE INVENTION

The present invention relates to the treatment of HIV comprisingadministering to a mammal in need of such treatment an effective amountof a CCR5 antagonist represented by the structural formula I:

or a pharmaceutically acceptable salt thereof, wherein

R is R⁸-phenyl, R⁸-pyridyl, R⁸-thiophenyl or R⁸-naphthyl;

R¹ is hydrogen or C₁-C₆ alkyl;

R² is R⁹, R¹⁰, R¹¹-phenyl; R⁹, R¹⁰, R¹¹-substituted 6-memberedheteroaryl; R⁹, R¹⁰, R¹¹-substituted 6-membered heteroaryl N-oxide;R¹², R¹³-substituted 5-membered heteroaryl; naphthyl; fluorenyl;diphenylmethyl

R³ is hydrogen, C₁-C₆ alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl, C₃-C₁₀cycloalkyl, C₃-C₁₀ cycloalkyl(C₁-C₆)alkyl, R⁸-phenyl,R⁸-phenyl(C₁-C₆)alkyl, R⁸-naphthyl, R⁸-naphthyl(C₁-C₆)alkyl,R⁸-heteroaryl or R⁸-heteroaryl(C₁-C₆)alkyl;

R⁴, R⁵, R⁷ and R¹³ are independently selected from the group consistingof hydrogen and (C₁-C₆)-alkyl;

R⁶ is hydrogen, C₁-C₆ alkyl or C₂-C₆ alkenyl;

R⁸ is 1 to 3 substituents independently selected from the groupconsisting of hydrogen, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, —CF₃, CF₃O—,CH₃C(O)—, —CN, CH₃SO₂—, CF₃SO₂—, R¹⁴-phenyl, R¹⁴-benzyl, CH₃C(═NOCH₃),CH₃C(═NOCH₂CH₃),

—NH₂, —NHCOCF₃, —NHCONH(C₁-C₆ alkyl), —NHCO(C₁-C₆ alkyl), —NHSO₂(C₁-C₆alkyl), 5-membered heteroaryl and

wherein X is —O—, —NH— or —N(CH₃)—;

R⁹ and R¹⁰ are independently selected from the group consisting of(C₁-C₆)alkyl, halogen, —NR¹⁷R¹⁸, —OH, —CF₃, —OCH₃, —O-acyl, —OCF₃ and—Si(CH₃)₃;

R¹¹ is R⁹, hydrogen, phenyl, —NO₂, —CN, —CH₂F, —CHF₂, —CHO, —CH═NOR¹⁷,pyridyl, pyridyl N-oxide, pyrimidinyl, pyrazinyl, —N(R¹⁷)CONR¹⁸R¹⁹,—NHCONH(chloro-(C₁-C₆)alkyl), —NHCONH((C₃-C₁)cycloalkyl(C₁-C₆)alkyl),—NHCO(C₁-C₆)alkyl, —NHCOCF₃, —NHSO₂N((C₁-C₆)alkyl)₂, —NHSO₂(C₁-C₆)alkyl,—N(SO₂CF₃)₂, —NHCO₂(C₁-C₆)alkyl, C₃-C₁₀ cycloalkyl, —SR²⁰, —SOR²⁰,—SO₂R²⁰, —SO₂NH(C₁-C₆ alkyl), —OSO₂(C₁-C₆)alkyl, —OSO₂CF₃,hydroxy(C₁-C₆)alkyl, —CON R¹⁷R¹⁸, —CON(CH₂CH₂—O—CH₃)₂,—OCONH(C₁-C₆)alkyl, —CO₂R¹⁷, —Si(CH₃)₃ or —B(OC(CH₃)₂)₂;

R¹² is (C₁-C₆)alkyl, —NH₂ or R¹⁴-phenyl;

R¹⁴ is 1 to 3 substituents independently selected from the groupconsisting of hydrogen, (C₁-C₆) alkyl, —CF₃, —CO₂R₁₇, —CN, (C₁-C₆)alkoxyand halogen;

R¹⁵ and R¹⁶ are independently selected from the group consisting ofhydrogen and C₁-C₆ alkyl, or R¹⁵ and R¹⁶ together are a C₂-C₅ alkylenegroup and with the carbon to which they are attached form a spiro ringof 3 to 6 carbon atoms;

R¹⁷, R¹⁸ and R¹⁹ are independently selected from the group consisting ofH and C₁-C₆ alkyl; and

R²⁰ is C₁-C₆ alkyl or phenyl.

Preferred are compounds of formula I wherein R is R⁸-phenyl orR⁸-naphthyl, especially wherein R⁸ is a single substituent, andespecially wherein the R⁸ substituent is in the 4-position. ForR⁸-phenyl, preferred R⁸ substituents are —CF₃, —OCF₃, CH₃SO₂—, CH₃CO—,CH₃C(═NOCH₃)—, Br and I. For R⁸-naphthyl, R⁸ is preferably C₁-C₆ alkoxy.Also preferred are compounds of formula I wherein R³ is hydrogen,(C₁-C₆) alkyl, R⁸-phenyl. R⁸-benzyl or R⁸-pyridyl; more preferreddefinitions for R³ are methyl, ethyl, phenyl, benzyl and pyridyl. R¹ ispreferably hydrogen. For compounds of formula I, R⁶ is preferablyhydrogen or methyl, especially methyl. R⁴ is preferably methyl; R⁵ andR⁷ are each preferably hydrogen.

In compounds of formula I, R² is preferably R⁹, R¹⁰, R¹¹-phenyl, R⁹,R¹⁰, R¹¹-pyridyl or an N-oxide thereof, or R⁹, R¹⁰, R¹¹-pyrimidyl. WhenR² is pyridyl, it is preferably 3- or 4-pyridyl, and when pyrimidyl, itis preferably 5-pyrimidyl. The R⁹ and R¹⁰ substituents are preferablyattached to carbon ring members adjacent to the carbon joining the ringto the rest of the molecule and the R¹¹ substituent can be attached toany of the remaining unsubstituted carbon ring members, for example asshown in the following structures:

Preferred R⁹ and R¹⁰ substituents are: (C₁-C₆)alkyl, especially methyl;halogen, especially chloro or bromo, —OH and —NH₂. When R² is phenyl,R¹¹ is preferably hydrogen or —OH; when R² is pyridyl, R¹¹ is preferablyhydrogen; and when R² is pyrimidyl, R¹¹ is preferably hydrogen, methylor phenyl. Examples of particularly preferred R² groups are as follows:

Also claimed are novel CCR5 antagonist compounds represented by thestructural formula II

or a pharmaceutically acceptable salt thereof, wherein(1) R^(a) is R^(8a)-phenyl, R^(8b)-pyridyl, R^(8b)-thiophenyl orR⁸-naphthyl;

R¹ is hydrogen or C₁-C₆ alkyl;

R² is R⁹, R¹⁰, R¹¹-phenyl; R⁹, R¹⁰, R¹¹-substituted 6-memberedheteroaryl;

R⁹, R¹⁰, R¹¹-substituted 6-membered heteroaryl N-oxide;

R¹², R¹³-substituted 5-membered heteroaryl; naphthyl; fluorenyl;diphenylmethyl,

R³ is hydrogen, C₁-C₆ alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl, C₃-C₁₀cycloalkyl, C₃-C₁₀ cycloalkyl(C₁-C₆)alkyl, R⁸-phenyl,R⁸-phenyl(C₁-C₆)alkyl, R⁸-naphthyl, R⁸-naphthyl(C₁-C₆)alkyl,R⁸-heteroaryl or R⁸-heteroaryl(C₁-C₆)alkyl;

R⁴, R⁵, R⁷ and R¹³ are independently selected from the group consistingof hydrogen and (C₁-C₆)-alkyl;

R⁶ is hydrogen, C₁-C₆ alkyl or C₂-C₆ alkenyl;

R⁸ is 1 to 3 substituents independently selected from the groupconsisting of hydrogen, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, —CF₃, CF₃O—,CH₃C(O)—, —CN, CH₃SO₂—CF₃SO₂—, R¹⁴-phenyl, R¹⁴-benzyl, CH₃C(═NOCH₃),CH₃C(═NOCH₂CH₃),

—NH₂, —NHCOCF₃, —NHCONH(C₁-C₆ alkyl), —NHCO(C₁-C₆ alkyl), —NHSO₂(C₁-C₆alkyl), 5-membered heteroaryl and

wherein X is —O—, —NH— or —N(CH₃)—;

R^(8a) is 1 to 3 substituents independently selected from the groupconsisting of hydrogen, halogen, —CF₃, CF₃O—, —CN, CF₃SO₂—, R¹⁴-phenyl,—NHCOCF₃, 5 membered heteroaryl and

wherein X is as defined above;

R^(8b) is 1 to 3 substituents independently selected from the groupconsisting of hydrogen, halogen, —CF₃, CF₃O—, CH₃C(O)—, —CN, CF₃SO₂—,R¹⁴-benzyl, CH₃C(═NOCH₃), CH₃C(═NOCH₂CH₃),

—NHCOCF₃, 5-membered heteroaryl and

wherein X is as defined above;

R⁹ and R¹⁰ are independently selected from the group consisting of(C₁-C₆)alkyl, halogen, —NR¹⁷R¹⁸, —OH, —CF₃, —OCH₃, —O-acyl, —OCF₃ and—Si(CH₃)₃;

R¹¹ is R⁹, hydrogen, phenyl, —NO₂, —CN, —CH₂F, —CHF₂, —CHO, —CH═NOR¹⁷,pyridyl, pyridyl N-oxide, pyrimidinyl, pyrazinyl, —N(R¹⁷)CONR¹⁸R¹⁹,—NHCONH(chloro-(C₁-C₆)alkyl), —NHCONH((C₃-C₁)cycloalkyl(C₁-C₆)alkyl),—NHCO(C₁-C₆)alkyl, —NHCOCF₃, —NHSO₂N((C₁-C₆)alkyl)₂, —NHSO₂(C₁-C₆)alkyl,—N(SO₂CF₃)₂, —NHCO₂(C₁-C₆)alkyl, C₃-C₁₀ cycloalkyl, —SR²⁰, —SOR²⁰,—SO₂R²⁰, —SO₂NH(C₁-C₆ alkyl), —OSO₂(C₁-C₆)alkyl, —OSO₂CF₃,hydroxy(C₁-C₆)alkyl, —CON R¹⁷R¹⁸, —CON(CH₂CH₂—O—CH₃)₂,—OCONH(C₁-C₆)alkyl, —CO₂R¹⁷, —Si(CH₃)₃ or —B(OC(CH₃)₂)₂;

R¹² is (C₁-C₆)alkyl, —NH₂ or R¹⁴-phenyl;

R¹⁴ is 1 to 3 substituents independently selected from the groupconsisting of hydrogen, (C₁-C₆) alkyl, —CF₃, —CO₂R₁₇, —CN, (C₁-C₆)alkoxyand halogen;

R¹⁵ and R¹⁶ are independently selected from the group consisting ofhydrogen and C₁-C₆ alkyl, or R¹⁵ and R¹⁶ together are a C₂-C₅ alkylenegroup and with the carbon to which they are attached form a spiro ringof 3 to 6 carbon atoms;

R¹⁷, R¹⁸ and R¹⁹ are independently selected from the group consisting ofH and C₁-C₆ alkyl; and

R²⁰ is C₁-C₆ alkyl or phenyl; or

(2) R^(a) is R⁸-phenyl, R⁸-pyridyl or R⁸-thiophenyl;

R² is fluorenyl, diphenylmethyl,

and R¹, R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶,R¹⁷, R¹⁸, R¹⁹ and R²⁰ are as defined in (1).

Preferred compounds of formula II are those defined in (1).

More preferred are those of formula II(1) wherein R^(a) is R^(8a)-phenylor R⁸-naphthyl, wherein R^(8a) is —CF₃, CF₃O— or halogen and R⁸ is C₁-C₆alkoxy. The R^(8a) or R⁸ substituent is preferably a single substituent;it is especially preferred that the R^(8a) or R⁸ substituent is in the4-position. Also preferred are compounds of formula II(1) wherein R³ ishydrogen, (C₁-C₆) alkyl, R⁸-phenyl. R⁸-benzyl or R⁸-pyridyl; morepreferred definitions for R³ are methyl, ethyl, phenyl, benzyl andpyridyl. R¹ is preferably hydrogen. For compounds of formula II(1), R⁶is preferably hydrogen or methyl, especially methyl. R⁴ is preferablymethyl; R⁵ and R⁷ are each preferably hydrogen.

R² in formula II(1) is preferably as defined for formula I, i.e., R⁹,R¹⁰, R¹¹-phenyl, R⁹, R¹⁰, R¹¹-pyridyl or an N-oxide thereof, or R⁹, R¹⁰,R¹¹-pyrimidyl, wherein the R⁹, R¹⁰, R¹¹-substitution is as defined abovefor preferred compounds of formula I.

Another aspect of the invention is a pharmaceutical composition fortreatment of HIV comprising an effective amount of a CCR5 antagonist offormula II in combination with a pharmaceutically acceptable carrier.Another aspect of the invention is a pharmaceutical composition fortreatment of solid organ transplant rejection, graft v. host disease,arthritis, rheumatoid arthritis, inflammatory bowel disease, atopicdermatitis, psoriasis, asthma, allergies or multiple sclerosiscomprising an effective amount of a CCR5 antagonist of formula II incombination with a pharmaceutically acceptable carrier.

Yet another aspect of this invention is a method of treatment of HIVcomprising administering to a human in need of such treatment aneffective amount of a CCR5 antagonist compound of formula II. Anotheraspect of the invention is a method of treatment of solid organtransplant rejection, graft v. host disease, arthritis, rheumatoidarthritis, inflammatory bowel disease, atopic dermatitis, psoriasis,asthma, allergies or multiple sclerosis comprising administering to ahuman in need of such treatment an effective amount of a CCR5 antagonistcompound of formula I or II.

Still another aspect of this invention is the use of a CCR5 antagonistof formula I or II of this invention in combination with one or moreantiviral or other agents useful in the treatment of HumanImmunodeficiency Virus for the treatment of AIDS. Still another aspectof this invention is the use of a CCR5 antagonist of formula I or II ofthis invention in combination with one or more other agents useful inthe treatment of solid organ transplant rejection, graft v. hostdisease, inflammatory bowel disease, rheumatoid arthritis or multiplesclerosis. The CCR5 and antiviral or other agents which are componentsof the combination can be administered in a single dosage form or theycan be administered separately; a kit comprising separate dosage formsof the actives is also contemplated.

DESCRIPTION OF DRAWINGS

FIG. 1 shows biotransformation of Vicriviroc in human, monkey and ratfollowing a single oral dose of ¹⁴C-VIC.

FIG. 2 shows comparison of representative radiochromatographic profilesof pooled plasma extract following a single oral administration ofVicriviroc to healthy male volunteers, male monkeys and rats

FIG. 3 shows comparison of representative radiochromatographic profilesof pooled urine following a single oral administration of Vicriviroc tohealthy male volunteers, male monkeys and rats.

FIG. 4 shows comparison of representative radiochromatographic profilesof pooled fecal extract following a single oral administration ofVicriviroc to healthy male volunteers, male monkeys and rats.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the following terms are used as defined below unlessotherwise indicated.

Alkyl represents straight and branched carbon chains and contains fromone to six carbon atoms.

Alkenyl represents C₂-C₆ carbon chains having one or two unsaturatedbonds, provided that two unsaturated bonds are not adjacent to eachother.

Substituted phenyl means that the phenyl group can be substituted at anyavailable position on the phenyl ring.

Acyl means a radical of a carboxylic acid having the formulaalkyl-C(O)—, aryl-C(O)—, aralkyl-C(O)—, (C₃-C₇)cycloalkyl-C(O)—,(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl-C(O)—, and heteroaryl-C(O)—, whereinalkyl and heteroaryl are as defined herein; aryl is R¹⁴-phenyl orR¹⁴-naphthyl; and aralkyl is aryl-(C₁-C₆)alkyl, wherein aryl is asdefined above.

Heteroaryl represents cyclic aromatic groups of 5 or 6 atoms or bicyclicgroups of 11 to 12 atoms having 1 or 2 heteroatoms independentlyselected from O, S or N, said heteroatom(s) interrupting a carbocyclicring structure and having a sufficient number of delocalized pielectrons to provide aromatic character, provided that the rings do notcontain adjacent oxygen and/or sulfur atoms. For 6-membered heteroarylrings, carbon atoms can be substituted by R⁹, R¹⁰ or R¹¹ groups.Nitrogen atoms can form an N-oxide. All regioisomers are contemplated,e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl. Typical 6-membered heteroarylgroups are pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and the N-oxidesthereof. For 5-membered heteroaryl rings, carbon atoms can besubstituted by R¹² or R¹³ groups. Typical 5-membered heteroaryl ringsare furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, imidazolyl,pyrazolyl and isoxazolyl. 5-Membered rings having one heteroatom can bejoined through the 2- or 3-position; 5-membered rings having twoheteroatoms are preferably joined through the 4-position. Bicyclicgroups typically are benzo-fused ring systems derived from theheteroaryl groups named above, e.g. quinolyl, phthalazinyl,quinazolinyl, benzofuranyl, benzothienyl and indolyl.

Preferred points of substitution for 6-membered heteroaryl rings at R²are described above. When R² is a 5-membered heteroaryl group, the R¹²and R¹³ substituents are preferably attached to carbon ring membersadjacent to the carbon joining the ring to the rest of the molecule, andR¹² is preferably alkyl; however, if a heteroatom is adjacent to thecarbon joining the ring to the rest of the molecule (i.e., as in2-pyrrolyl), R¹² is preferably attached to a carbon ring member adjacentto the carbon joining the ring to the rest of the molecule.

Halogen represents fluoro, chloro, bromo and iodo.

Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. The term “prodrug”, as employed herein, denotes acompound that is a drug precursor which, upon administration to asubject, undergoes chemical conversion by metabolic or chemicalprocesses to yield a compound of Formula 1 or a salt and/or solvatethereof. A discussion of prodrugs is provided in T. Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems (1987) Volume 14 of theA.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design,(1987) Edward B. Roche, ed., American Pharmaceutical Association andPergamon Press, both of which are incorporated herein by referencethereto.

“Solvate” means a physical association of a compound of this inventionwith one or more solvent molecules. This physical association involvesvarying degrees of ionic and covalent bonding, including hydrogenbonding. In certain instances the solvate will be capable of isolation,for example when one or more solvent molecules are incorporated in thecrystal lattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolatable solvates. Non-limiting examples ofsuitable solvates include ethanolates, methanolates, and the like.“Hydrate” is a solvate wherein the solvent molecule is H₂O. In general,the solvated forms are equivalent to the unsolvated forms and areintended to be encompassed within the scope of this invention.

Pharmaceutically acceptable esters of the present compounds include thefollowing groups: (1) carboxylic acid esters obtained by esterificationof the hydroxy groups, in which the non-carbonyl moiety of thecarboxylic acid portion of the ester grouping is selected from straightor branched chain alkyl (for example, acetyl, n-propyl, t-butyl, orn-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (forexample, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (forexample, phenyl optionally substituted with, for example, halogen,C₁₋₄alkyl, or C₁₋₄alkoxy or amino); (2) sulfonate esters, such as alkyl-or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters(for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5)mono-, di- or triphosphate esters. The phosphate esters may be furtheresterified by, for example, a C₁₋₂₀ alcohol or reactive derivativethereof, or by a 2,3-di (C₆₋₂₄)acyl glycerol.

One or more, preferaby one to four, antiviral agents useful inanti-HIV-1 therapy may be used in combination with a CCR5 antagonist ofthe present invention. The antiviral agent or agents may be combinedwith the CCR5 antagonist in a single dosage form, or the CCR5 antagonistand the antiviral agent or agents may be administered simultaneously orsequentially as separate dosage forms. The antiviral agents contemplatedfor use in combination with the compounds of the present inventioncomprise nucleoside and nucleotide reverse transcriptase inhibitors,non-nucleoside reverse transcriptase inhibitors, protease inhibitors andother antiviral drugs listed below not falling within theseclassifications. In particular, the combinations known as HAART (HighlyActive Antiretroviral Therapy) are contemplated for use in combinationwith the CCR5 antagonists of this invention.

The term “nucleoside and nucleotide reverse transcriptase inhibitors”(“NRTI” s) as used herein means nucleosides and nucleotides andanalogues thereof that inhibit the activity of HIV-1 reversetranscriptase, the enzyme which catalyzes the conversion of viralgenomic HIV-1 RNA into proviral HIV-1 DNA.

Typical suitable NRTIs include zidovudine (AZT) available under theRETROVIR tradename from Glaxo-Wellcome Inc., Research Triangle, N.C.27709; didanosine (ddI) available under the VIDEX tradename fromBristol-Myers Squibb Co., Princeton, N.J. 08543; zalcitabine (ddC)available under the HIVID tradename from Roche Pharmaceuticals, Nutley,N.J. 07110; stavudine (d4T) available under the ZERIT trademark fromBristol-Myers Squibb Co., Princeton, N.J. 08543; Iamivudine (3TC)available under the EPIVIR tradename from Glaxo-Wellcome ResearchTriangle, N.C. 27709; abacavir (1592U89) disclosed in WO96/30025 andavailable under the ZIAGEN trademark from Glaxo-Wellcome ResearchTriangle, N.C. 27709; adefovir dipivoxil [bis(POM)-PMEA] available underthe PREVON tradename from Gilead Sciences, Foster City, Calif. 94404;Iobucavir (BMS-180194), a nucleoside reverse transcriptase inhibitordisclosed in EP-0358154 and EP-0736533 and under development byBristol-Myers Squibb, Princeton, N.J. 08543; BCH-10652, a reversetranscriptase inhibitor (in the form of a racemic mixture of BCH-10618and BCH-10619) under development by Biochem Pharma, Laval, Quebec H7V,4A7, Canada; emitricitabine [(−)-FTC] licensed from Emory Universityunder Emory Univ. U.S. Pat. No. 5,814,639 and under development byTriangle Pharmaceuticals, Durham, N.C. 27707; beta-L-FD4 (also calledbeta-L-D4C and named beta-L-2′,3′-dideoxy-5-fluoro-cytidene) licensed byYale University to Vion Pharmaceuticals, New Haven Conn. 06511; DAPD,the purine nucleoside, (−)-beta-D-2,6,-diamino-purine dioxolanedisclosed in EP 0656778 and licensed by Emory University and theUniversity of Georgia to Triangle Pharmaceuticals, Durham, N.C. 27707;and Iodenosine (FddA),9-(2,3-dideoxy-2-fluoro-b-D-threo-pentofuranosyl)adenine, a acid stablepurine-based reverse transcriptase inhibitor discovered by the NIH andunder development by U.S. Bioscience Inc., West Conshohoken, Pa. 19428.

The term “non-nucleoside reverse transcriptase inhibitors” (“NNRTI”s) asused herein means non-nucleosides that inhibit the activity of HIV-1reverse transcriptase.

Typical suitable NNRTIs include nevirapine (BI-RG-587) available underthe VIRAMUNE tradename from Boehringer Ingelheim, the manufacturer forRoxane Laboratories, Columbus, Ohio 43216; delaviradine (BHAP, U-90152)available under the RESCRIPTOR tradename from Pharmacia & Upjohn Co.,Bridgewater N.J. 08807; efavirenz (DMP-266) a benzoxazin-2-one disclosedin WO94/03440 and available under the SUSTIVA tradename from DuPontPharmaceutical Co., Wilmington, Del. 19880-0723; PNU-142721, afuropyridine-thio-pyrimide under development by Pharmacia and Upjohn,Bridgewater N.J. 08807; AG-1549 (formerly Shionogi # S-1153);5-(3,5-dichlorophenyl)-thio-4-isopropyl-1-(4-pyridyl)methyl-1H-imidazol-2-ylmethylcarbonate disclosed in WO 96/10019 and under clinical development byAgouron Pharmaceuticals, Inc., LaJolla Calif. 92037-1020; MKC-442(1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione)discovered by Mitsubishi Chemical Co. and under development by TrianglePharmaceuticals, Durham, N.C. 27707; and (+)-calanolide A (NSC-675451)and B, coumarin derivatives disclosed in NIH U.S. Pat. No. 5,489,697,licensed to Med Chem Research, which is co-developing (+) calanolide Awith Vita-invest as an orally administrable product.

The term “protease inhibitor” (“PI”) as used herein means inhibitors ofthe HIV-1 protease, an enzyme required for the proteolytic cleavage ofviral polyprotein precursors (e.g., viral GAG and GAG Pol polyproteins),into the individual functional proteins found in infectious HIV-1. HIVprotease inhibitors include compounds having a peptidomimetic structure,high molecular weight (7600 daltons) and substantial peptide character,e.g. CRIXIVAN(available from Merck) as well as nonpeptide proteaseinhibitors e.g., VIRACEPT (available from Agouron).

Typical suitable PIs include saquinavir (Ro 31-8959) available in hardgel capsules under the INVIRASE tradename and as soft gel capsules underthe FORTOUASE tradename from Roche Pharmaceuticals, Nutley, N.J.07110-1199; ritonavir (ABT-538) available under the NORVIR tradenamefrom Abbott Laboratories, Abbott Park, Ill. 60064; indinavir (MK-639)available under the CRIXIVAN tradename from Merck & Co., Inc., WestPoint, Pa. 19486-0004; nelfnavir (AG-1343) available under the VIRACEPTtradename from Agouron Pharmaceuticals, Inc., LaJolla Calif. 92037-1020;amprenavir (141W94), tradename AGENERASE, a non-peptide proteaseinhibitor under development by Vertex Pharmaceuticals, Inc., Cambridge,Mass. 02139-4211 and available from Glaxo-Wellcome, Research Triangle,N.C. under an expanded access program; lasinavir (BMS-234475) availablefrom Bristol-Myers Squibb, Princeton, N.J. 08543 (originally discoveredby Novartis, Basel, Switzerland (CGP-61755); DMP-450, a cyclic ureadiscovered by Dupont and under development by Triangle Pharmaceuticals;BMS-2322623, an azapeptide under development by Bristol-Myers Squibb,Princeton, N.J. 08543, as a 2nd-generation HIV-1 PI; ABT-378 underdevelopment by Abbott, Abbott Park, Ill. 60064; and AG-1549 an orallyactive imidazole carbamate discovered by Shionogi (Shionogi #S-1153) andunder development by Agouron Pharmaceuticals, Inc., LaJolla Calif.92037-1020.

Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12,pentafuside and Yissum Project No. 11607. Hydroxyurea (Droxia), aribonucleoside triphosphate reductase inhibitor, the enzyme involved inthe activation of T-cells, was discovered at the NCI is underdevelopment by Bristol-Myers Squibb; in preclinical studies, it wasshown to have a synergistic effect on the activity of didanosine and hasbeen studied with stavudine. IL-2 is disclosed in Ajinomoto EP-0142268,Takeda EP-0176299, and Chiron U.S. Pat. Nos. RE 33653, 4530787, 4569790,4604377, 4748234, 4752585, and 4949314 is available under the PROLEUKIN(aldesleukin) tradename from Chiron Corp., Emeryville, Calif. 94608-2997as a lyophilized powder for IV infusion or sc administration uponreconstitution and dilution with water; a dose of about 1 to about 20million IU/day, sc is preferred; a dose of about 15 million IU/day, scis more preferred. IL-12 is disclosed in WO96/25171 and is availablefrom Roche Pharmaceuticals, Nutley, N.J. 07110-1199 and American HomeProducts, Madison, N.J. 07940; a dose of about 0.5 microgram/kg/day toabout 10 microgram/kg/day, sc is preferred. Pentafuside (DP-178, T-20) a36-amino acid synthetic peptide, disclosed in U.S. Pat. No. 5,464,933licensed from Duke University to Trimeris which is developingpentafuside in collaboration with Duke University; pentafuside acts byinhibiting fusion of HIV-1 to target membranes. Pentafuside (3-100mg/day) is given as a continuous sc infusion or injection together withefavirenz and 2 PI's to HIV-1 positive patients refractory to a triplecombination therapy; use of 100 mg/day is preferred. Yissum Project No.11607, a synthetic protein based on the HIV-1 Vif protein, is underpreclinical development by Yissum Research Development Co., Jerusalem91042, Israel. Ribavirin, 1-β-D-ribofuranosyl-1H-1,2,4-triazole-3carboxamide, is available from ICN Pharmaceuticals, Inc., Costa Mesa,Calif.; its manufacture and formulation are described in U.S. Pat. No.4,211,771.

The term “anti-HIV-1 therapy” as used herein means any anti-HIV-1 drugfound useful for treating HIV-1 infections in man alone, or as part ofmultidrug combination therapies, especially the HAART triple andquadruple combination therapies. Typical suitable known anti-HIV-1therapies include, but are not limited to multidrug combinationtherapies such as (i) at least three anti-HIV-1 drugs selected from twoNRTIs, one PI, a second PI, and one NNRTI; and (ii) at least twoanti-HIV-1 drugs selected from, NNRTIs and P is. Typical suitableHAART—multidrug combination therapies include:

(a) triple combination therapies such as two NRTIs and one PI; or (b)two NRTIs and one NNRTI; and (c) quadruple combination therapies such astwo NRTIs, one PI and a second PI or one NNRTI. In treatment of naivepatients, it is preferred to start anti-HIV-1 treatment with the triplecombination therapy; the use of two NRTIs and one PI is preferred unlessthere is intolerance to P is. Drug compliance is essential. The CD4⁺ andHIV-1-RNA plasma levels should be monitored every 3-6 months. Shouldviral load plateau, a fourth drug, e.g., one PI or one NNRTI could beadded. See the table below wherein typical therapies are furtherdescribed:

Anti-HIV-1 Multi Drug Combination Therapies

A. Triple Combination Therapies

1. Two NRTIs¹+one PI²

2. Two NRTIs¹+one NNRTI³

B. Quadruple Combination Therapies⁴

Two NRTIs+one PI+a second PI or one NNRTI

C. ALTERNATIVES:⁵

Two NRTI¹

One NRTI⁵+one PI²

Two PIs⁶±one NRTI⁷ or NNRTI³

One PI²+one NRTI⁷+one NNRTI³

Footnotes to Table

1. One of the following: zidovudine+lamivudine; zidovudine+didanosine;stavudine+lamivudine; stavudine+didanosine; zidovudine+zalcitabine

2. Indinavir, nelfinavir, ritonavir or saquinavir soft gel capsules.

3. Nevirapine or delavirdine.

4. See A-M. Vandamne et al Antiviral Chemistry & Chemotherapy 9:187 at p193-197 and FIGS. 1+2.

5. Alternative regimens are for patients unable to take a recommendedregimen because of compliance problems or toxicity, and for those whofail or relapse on a recommended regimen. Double nucleoside combinationsmay lead to HIV-resistance and clinical failure in many patients.

6. Most data obtained with saquinavir and ritonavir (each 400 mg bid).

7. Zidovudine, stavudine or didanosine.

Agents known in the treatment of rheumatoid arthritis, transplant andgraft v. host disease, inflammatory bowel disease and multiple sclerosiswhich can be administered in combination with the CCR5 antagonists ofthe present invention are as follows:

solid organ transplant rejection and graft v. host disease: immunesuppressants such as cyclosporine and Interleukin-10 (IL-10),tacrolimus, antilymphocyte globulin, OKT-3 antibody, and steroids;

inflammatory bowel disease: IL-10 (see U.S. Pat. No. 5,368,854),steroids and azulfidine;

rheumatoid arthritis: methotrexate, azathioprine, cyclophosphamide,steroids and mycophenolate mofetil;

multiple sclerosis: interferon-beta, interferon-alpha, and steroids.

Certain compounds of the invention may exist in different isomeric forms(e.g., enantiomers, diastereoisomers, atropisomers and rotamers). Theinvention contemplates all such isomers both in pure form and inadmixture, including racemic mixtures.

Certain compounds will be acidic in nature, e.g. those compounds whichpossess a carboxyl or phenolic hydroxyl group. These compounds may formpharmaceutically acceptable salts. Examples of such salts may includesodium, potassium, calcium, aluminum, gold and silver salts. Alsocontemplated are salts formed with pharmaceutically acceptable aminessuch as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine andthe like.

Certain basic compounds also form pharmaceutically acceptable salts,e.g., acid addition salts. For example, the pyrido-nitrogen atoms mayform salts with strong acid, while compounds having basic substituentssuch as amino groups also form salts with weaker acids. Examples ofsuitable acids for salt formation are hydrochloric, sulfuric,phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric,succinic, ascorbic, maleic, methanesulfonic and other mineral andcarboxylic acids well known to those in the art. The salts are preparedby contacting the free base form with a sufficient amount of the desiredacid to produce a salt in the conventional manner. The free base formsmay be regenerated by treating the salt with a suitable dilute aqueousbase solution such as dilute aqueous NaOH, potassium carbonate, ammoniaand sodium bicarbonate. The free base forms differ from their respectivesalt forms somewhat in certain physical properties, such as solubilityin polar solvents, but the acid and base salts are otherwise equivalentto their respective free base forms for purposes of the invention.

All such acid and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

Compounds of the invention can be made by the procedures known in theart, for example by the procedures described in the following reactionschemes, by the methods described in the examples below, and by usingthe methods described in WO96/26196 and WO98/05292.

The following solvents and reagents may be referred to herein by theabbreviations indicated: tetrahydrofuran (THF); ethanol (EtOH); methanol(MeOH); acetic acid (HOAc or AcOH); ethyl acetate (EtOAc);N,N-dimethylformamide (DMF); trifluoroacetic acid (TFA);1-hydroxy-benzotriazole (HOBT); m-chloroperbenzoic acid (MCPBA);triethylamine (Et₃N); diethyl ether (Et₂O); dimethylsulfoxide (DMSO);and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (DEC).RT is room temperature, and TLC is thin-layer chromatography. Me ismethyl, Et is ethyl, Pr is propyl, Bu is butyl, Ph is phenyl, and Ac isacetyl.

Reagents and conditions: a: R⁴CH(OSO₂CF₃)CO₂CH₃, base (e.g., K₂CO₃); b:ClCH₂COCl; c: NH₃; d: NaBH₄—BF₃; e: N-Boc-4-piperidone, NaBH(OAc)₃; f:CF₃CO₂H; g: acylation; h: N-Boc-4-piperidone, Ti(OPr-i)₄, Et₂AlCN; i:CH₃MgBr.

In Scheme 1, a benzylamine (1), wherein R and R³ are as defined aboveand R¹ is hydrogen, is converted via (2) and (3) to the diketopiperazine(4), wherein R⁴ is as defined above, which is reduced to the piperazine(5). Depending upon the desired R⁶ substituent, this is processed in twoways. Reductive amination gives (6), which can be deprotected to (7) andfinally acylated to the compounds of formula IA wherein R⁵ and R⁶ are H;alternatively, a modified Strecker reaction on (5) gives theaminonitrile (8), which, after treatment with methyl Grignard to give(9), deprotection to (10) and final N-acylation affords the compounds offormula IB wherein R⁵ is H and R⁶ is methyl. Acylation of (7) and (10)is carried out under standard conditions, e.g., with a compound R²COOHand reagents such as DEC and HOBT. Use of a chiral compound of formulaI, e.g., (S)-methyl 4-substituted benzylamine, and a chiral lactate instep a, e.g., methyl (R)-lactate triflate, will result in chiralcompounds of formulas IA and IB.

Reagents: j: oxaborazolidine, BH₃; k: CH₃SO₂Cl, base; I: CF₃CO₂H.

In Scheme 2, the compounds are prepared by an alkylation process on apre-formed piperazine derivative. For example, preferred compounds withthe S,S stereochemistry may be obtained in this way by chiral reductionof a ketone (11) to the alcohol (12), activation as the mesylate, anddisplacement with inversion by treatment with a suitable piperazine,which may either be mono-protected, in which case final elaborationrequires deprotection followed by the steps described in (e)-(g) inScheme 1 to obtain IC, or may be elaborated prior to the displacementstep, in which case the final steps are (f) and (g) (deprotection andacylation) as in Scheme 1 to obtain ID.

For compounds where R³ and R¹ are each H, either the alkylation route ofScheme 2 or a reductive amination method as typified in Scheme 3 can beused.

For diaryl compounds, wherein R and R³ are each aryl, an alkylationmethod as typified in Scheme 4 is preferrred.

piperazines of formula 14, especially those wherein R³ is C₂-C₆ alkyl orbenzyl, may also be obtained by a process wherein the

portion is introduced as shown above by an alkylation-decyanationsequence. The reaction is exemplified for compounds wherein R isCF₃O-phenyl, R¹ is hydrogen, R³ is ethyl and R⁴ is methyl, but usingappropriate starting materials, other compounds of formula 14 can besimilarly prepared.

Reagents: m: BOC₂O, base; n: R⁶MgBr; 0: CCl₃CO₂H, NaBH₃CN; p: CF₃CO₂H;q: NaBH₄, BF₃.

As shown in Scheme 6, compounds bearing an additional alkyl group at R⁵on the piperazine ring may be prepared from the diketopiperazineintermediates (4) of Scheme 1. (4) is activated by conversion to theN(t-butoxycarbonyl) compound (17); addition of a Grignard reagent andsequential reduction, deprotection and lactam reduction provides (21),which can be used to prepare compounds of formula I in the mannerdescribed for intermediate (5) in Scheme 1.

Many piperazines wherein R is R⁸-phenyl (or their Boc derivatives) shownin Scheme 1 can be obtained from a common intermediate, wherein R⁸ is I.Several examples are shown in the above scheme, wherein R⁸ is convertedto Cl, CN, —C(O)NH₂, H, Ph and p-ClC₆H₄CH₂—. Detailed procedures forthese conversions are provided in the examples below. The resultantpiperazine or BOC-piperazine is then treated as shown in Scheme 1.

Some compounds of the invention may be obtained by a Mannich method, asshown in the specific example of Scheme 8.

Compounds useful in this invention are exemplified by the followingpreparative examples, which should not be construed to limit the scopeof the disclosure. Alternative mechanistic pathways and analogousstructures within the scope of the invention may be apparent to thoseskilled in the art.

EXAMPLE 1

Step 1: Stir methyl R-lactate (5.0 g) in CH₂Cl₂ (40 ml) at −70° C. andadd trfluoromethanesulfonic anhydride (7.6 ml), then 2,6-lutidine (7.8ml). Remove the cooling, stir 0.5 h, wash with 2N HCl and add theorganic solution to (S)-methyl 4-bromobenzylamine (9.0 g) and K₂CO₃(11.2 g) in water (60 ml). Stir 20 h at RT, dry the organic phase overK₂CO₃, evaporate and chromatograph on silica gel with Et₂O—CH₂Cl₂ togive the desired product (7.50 g) as a thick oil.Step 2: Reflux the product of step 1 (7.5 g) in 1,2-dichloroethane (40ml) and ClCH₂COCl (5.0 ml) for 5 h, then evaporate and use the resultantresidue directly in the next step.Step 3: Stir the product of step 2 in DMSO (80 ml), water (10 ml) andNaI (8 g), cool in ice, add conc. NH₄OH solution (15 ml) and stir to RTfor 20 h. Add water (200 ml) dropwise, collect the solid, wash well withwater and dry at 70° C./5 mm to give the diketopiperazine, suitable forthe next step.Step 4: Stir a mixture of the product of step 3 (6.8 g),1,2-dimethoxyethane (60 ml) and NaBH₄ (3.4 g) under N₂, add BF₃.OEt₂(6.8 ml) dropwise, then heat at 100° C. for 10 h. Cool and add CH₃OH (20ml) dropwise, followed by conc. HCl (30 ml). Heat at 100° C. for 1 h.,cool, basify with excess 2N NaOH and extract with EtOAc. Dry over K₂CO₃and evaporate to obtain the piperazine (5.85 g), suitable for the nextstep.Step 5: Stir for 20 h. at RT a mixture of the product of step 4 (5.48g), N-Boc-4-piperidinone (4.32 g), HOAc (1.15 ml), CH₂Cl₂ (80 ml) andsodium triacetoxy-borohydride (NaBH(OAc)₃) (8.3 g). Add excess aqueousNa₂CO₃ solution slowly, stir for 0.5 h, separate and filter the organicphase through a pad of silca gel, washing with 10:1 CH₂Cl₂-Et₂O to eluteall of the product. Evaporate and dissolve the residue in Et₂O (100 ml).Stir and add a 4M solution of HCl in 1,4-dioxane (10 ml) dropwise.Collect the solid, wash with Et₂O, and stir with CH₂Cl₂ and excessaqueous NaOH. Dry the organic phase over K₂CO₃ and evaporate to obtainthe desired product (5.45 g).Step 6: Stir at RT for 2 h a mixture of the product of step 5 (1.5 g)and TFA (4 ml). Evaporate, dissolve in CH₂Cl₂ and wash with excess 1NNaOH solution. Dry over K₂CO₃ and evaporate to obtain the product (1.15g).Compound 1A: Following the standard procedure, react the product of step6 with 2,6-dimethylbenzoyl chloride in CH₂Cl₂ and aqueous NaOH, andconvert the product to the hydrochloride. Mp 185-192° C.(decomposition). HRMS found: 498.2130; MH⁺ Calc: 498.2120.Compound 1B: Following the standard procedure, couple the product ofstep 6 with 2-amino-6-methylbenzoic acid using HOBT and DEC withdiisopropylethylamine in DMF, purify the amide by preparative TLC andconvert to the hydrochloride. Mp 188-196° C. (decomposition). HRMSfound: 499.2069; MH⁺ Calc: 499.2072.Compound 1C: Following the above method, couple the product of step 6with 2-amino-6-chlorobenzoic acid and convert after purification to thehydrochloride. Mp 192-200° C. (decomposition). HRMS found: 519.1530; MH⁺Calc: 519.1526.

EXAMPLE 2

Step 1: Stir the product of Example 1, step 4 (1.00 g),N-t-butoxycarbonyl-4-piperidinone (0.77 g) and titanium (IV)isopropoxide (Ti(OiPr)₄) (1.00 g) for 20 h at RT in CH₂Cl₂ (15 ml),reflux for 3 h and cool to RT. Add diethylaluminum cyanide (Et₂AlCN)(4.2 ml of 1M toluene solution) and the stir for 5 days at RT under dryN₂. Workup in CH₂Cl₂-aq. NaOH, dry and evaporate the organic phase andchromatograph on silica gel with CH₂Cl₂-CH₃OH (100:1) to obtain thedesired product (0.72 g).Step 2: React the product of step 1 (0.70 g) in dry THF (15 ml) under N₂with CH₃MgBr (4 ml of 3M Et₂O solution) at RT for 20 h. Workup inEtOAc-water and filter the organic phase through silica gel, washingwith EtOAc. Evaporate to obtain the desired product (0.65 g).Step 3: Deprotect the product of step 2 with TFA according to theprocedure described in Example 1, step 6.Compound 2A: React the product of step 3 with dimethylbenzoyl chlorideas described in Example 1 and convert to the HCl salt. Mp 180-187° C.(decomposition). HRMS Found: 512.2272; MH+Calc: 512.2276.Compound 2B: React the product of step 3 with 2-amino-6-chlorobenzoicacid as described in Example 1, purify the crude product by preparativeTLC and convert to the HCl salt. Mp 195-200° C. (decomposition). HRMSFound: 535.1662; MH⁺ Calc: 535.1652.Compound 2C: React the product of step 3 with 2-hydroxy-6-methylbenzoicacid as described in Example 1, purify the crude product by preparativeTLC and convert to the HCl salt. Mp 206-210° C. (decomposition). HRMSFound: 514.2067; MH⁺ Calc: 514.2069.Compound 2D: React the product of step 3 with 2-amino-6-methylbenzoicacid using a procedure similar to that described in Example 1, purifythe crude product by preparative TLC and convert to the HCl salt. Mp202-209° C. (decomposition). HRMS Found: 513.2227; MH⁺ Calc: 513.2229.

EXAMPLE 3

Step 1: Reflux and stir a mixture of S-alanine methyl esterhydrochloride (14 g), anhydrous Na₂CO₃ (60 g), dry CH₃CN (125 ml),chlorodiphenylmethane (22.3 g) and NaI (5 g) for 6 hr. Cool, add ice-H₂Oand extract with Et₂O (350 ml, then 50 ml). Combine the Et₂O extractsand wash with portions of 1N aq. HCl: 200 ml, 100 ml, then 4×10 ml.Combine the aqueous acid extracts, stir and add excess Na₂CO₃ in smallpoprtions until the mixture is basic. Extract with Et₂O, dry over MgSO₄and evaporate to obtain the N-diphenylmethyl compound (23.2 g).Step 2: Reflux all of the above compound with ClCH₂COCl (10 ml) indichloroethane (60 ml) for 4 h. Evaporate, and cb-evaporate with toluene(20 ml). Dissolve the residue in CH₂Cl₂ (200 ml), stir for 0.5 h withactivated carbon (10 g), filter and evaporate. Stir the residue with icecooling in DMSO (200 ml) and gradually add concentrated aqueous NH₃ (100ml), then NaI (10 g). Stir at RT for 20 hr. Add iced water (500 ml),collect the solid, wash well with water, then with several smallportions of a 10:1 hexane-Et₂O mixture, and dry at 50° C. with highvacuum to obtain the solid diketopiperazine (15.5 g). Recrystallise asmall sample from CH₂Cl₂-hexanes: mp 186-188° C.; [α]_(D) ²⁰ =+272.60.Step 3: Stir the product of step 2 (4.0 g) in dimethoxyethane (40 ml)and NaBH₄ (1.6 g) under N₂ and add BF₃.OEt₂ (3.2 ml) slowly. Reflux for20 h. Cool and add CH₃OH (10 ml) dropwise, then conc. HCl (15 ml).Reflux for 2 h., and work up in excess 2N aq. NaOH and extract withCH₂Cl₂. Dry over K₂CO₃ and evaporate. Chromatograph on silica, elutingwith CH₂Cl₂-CH₃OH mixtures, and finally with 5:1:0.1 v/v/vCH₂Cl₂:CH₃OH:NH₄OH. Combine and evaporate the product fractions toobtain the desired product (1.95 g) as a pale yellow gum.Step 4: Stir a mixture of the product of step 3 (0.50 g),N-allyloxycarbonyl-4-piperidone (0.40 g), CH₂Cl₂ (5 ml) and NaBH(OAc)₃(0.70 g) at RT for 20 h. Work up in CH₂Cl₂ and excess aq. NaOH, dry overMgSO₄, evaporate and isolate the product by preparative TLC, elutingwith 10% Et₂O in CH₂Cl₂, to obtain the desired compound (0.80 g) as anoil, contaminated with a small amount of starting ketone, but suitablefor the next step.Step 5: Stir a mixture of the product of step 4 (0.80 g), CH₃CN (20 ml),water (5 ml) and piperidine (1.5 ml). Add tri(4-sulfophenyl)phosphine(0.072 g) and palladium (II) acetate (0.02 g) and stir at RT under N₂for 2 h. Work up with aqueous NaOH, extract with 5:1 v/v toluene:CH₂Cl₂,dry over K₂CO₃ and evaporate to obtain a yellow oil, suitable foracylation.Compound 3A: Stir and reflux a mixture of the product of step 5 (0.10g), N-(2,6-dimethoxybenzoyl)-4-piperidinone (0.10 g), CH₂Cl₂ (2 ml) andNaBH(OAc)₃ (0.15 g) for 2.5 h., cool, and work up with CH₂Cl₂ andaqueous NaOH. Dry over MgSO₄, evaporate and isolate the major product bypreparative TLC, eluting with 3:1 v/v Et₂O:CH₂Cl₂. Precipitate thehydrochoride to obtain the desired compound as the HCl salt (0.13 g). Mp173-177° C. (decomposition). HRMS Found: 482.3175; MH⁺ Calc: 482.3171.Compound 3B: Couple the product of step 5 with 2-amino-6-chlorobenzoicacid using DEC-HOBT as described in Example 1, isolate the product byPTLC and precipitate the hydrochloride to give compound 3B. Mp 188-195°C. (decomposition). HRMS Found: 503.2567; MH⁺ Calc: 503.2578.Compound 3C: Couple the product of step 5 with 2,4-dimethylnicotinicacid using DEC-HOBt as described above, isolate the product by PTLC andprecipitate the hydrochloride to give compound 3C. Mp 180-188° C.(decomposition). HRMS Found: 483.3114; MH⁺ Calc: 483.3124.

Using procedures similar to those described above, the followingcompounds were prepared:

EXAMPLE 4

Step 1: A solution of 4-trifluoromethyl acetophenone (1.88 g; 10 mmol)in dry THF (10 ml) was cooled in an ice bath and treated with freshlyprepared solid (S)-2-methyl oxaborolidine (0.54 g; 2 mmol). After 10min., a solution of 2M borane-methyl sulfide complex (3 ml; 6 mmol) inTHF was added dropwise over 5 min. TLC at the end of 30 min. showed thatthe starting material had been converted to a more polar product. Thereaction was quenched with about 5 ml of CH₃OH carefully untileffervescence stopped; volatiles were removed in vacuo. The residue wasdissolved in CH₂Cl₂ and washed with 1N HCl, water, 10% NaHCO₃ solutionand brine. Concentration in vacuo gave 2 g of a yellow gum. Flash silicagel chromatography (FSGC) using 10-20% EtOAc in hexanes furnished thedesired chiral alcohol (1.6 g; 84%) as a colorless oil.TLCR_(f)=0.6 in 25% EtOAc:hexanes.Step 2: To a solution of the product of step 1(1.55 g; 8.16 mmol) in 10ml of CH₂Cl₂ cooled in an ice bath were added Et₃N (2.3 ml; 16.32 mmol)and CH₃SO₂Cl (0.87 ml; 10.6 mmol) to form a turbid white solution. Thereaction was quenched with water and the organic product was extractedwith CH₂Cl₂, washing with water, 1N HCl, 10% NaHCO₃ solution and brine.Concentration in vacuo gave the chiral mesylate (2.1 g; 96%) as a paleyellow oil. TLC R_(f)=0.6 in 25% EtOAc:hexanes.Step 3: A solution of the product of step 2 (2.1 g; 7.8 mmol), the N-BOCprotected 2(S)-methyl piperazine (1.56 g; 7.8 mmol—prepared from thereaction of commercial 2(S)-methyl piperazine withN-(tert-butoxy-carbonyloxy)phthalimide) and 2,2,6,6-tetramethylpiperidine (1.34 ml; 8 mmol) in 14 ml of dry CN₃CN were heated at refluxuntil TLC indicated complete disappearance of the mesylate (16 h). Thereaction mixture was cooled to RT, diluted with CH₂Cl₂ (50 ml) andwashed with water (3×100 ml) and brine. The organic extract was driedover solid MgSO₄ and then concentrated to obtain 2.8 g of a yellow gum.FSGC (20% EtOAc in hexanes) served to isolate the desired(S,S)-diastereomer (1.5 g; 52%) and its benzylic epimer, the(R,S)-diastereomer (0.5 g; 17%) for a combined 69% yield. TLC R_(f)=0.75(S,S) and 0.56 (R,S) in 25% EtOAc:hexanes.Step 4: TFA (6 ml) was added to a solution of the product of step 3 in12 ml of CH₂Cl₂ and the resulting yellow-orange solution was stirred atRT for 8 h. The reaction was quenched by adding 1N NaOH solution toadjust the pH to 10. Extractive work up in CH₂Cl₂ gave 1.1 g of a yellowsyrup. FSGC using 10% CH₃OH in CH₂Cl₂ removed the less polar impurityand gradient elution with 1% Et₃N in 10% CH₃OH:CH₂Cl₂ was needed toelute the desired free amine of the (S,S) diastereomer. Yield=0.9 g(75%). TLC R_(f)=0.5 in 10% CH₃OH:CH₂Cl₂.Step 5: A colorless solution of the product of step 4 (0.9 g; 3.3 mmol),4-piperidinone (0.86 g; 4.3 mmol), NaB(OAc)₃H (1.05 g; 4.95 mmol) andglacial AcOH (80 μl) in 8 ml of CH₂Cl₂ was stirred at ambienttemperature for a day. TLC indicated absence of starting material. Thereaction mixture was diluted with 50 ml of CH₂Cl₂, washed with 1N NaOHsolution, water (2×) and brine. The CH₂Cl₂ extract was dried overanhydrous MgSO₄ and concentrated to obtain 1.7 g of yellow oil. FSGC(25% acetone in hexanes) was used to isolate the pure product (1.3 g;86%) as a white foam. TLC R_(f)=0.6 in 25% acetone/hexanes.Step 6: TFA (5 ml) was added to a solution of the product of step 5 (1.3g; 2.87 mmol) in CH₂Cl₂ (10 ml) and the resulting yellow orange solutionwas stirrred at RT for 7 h. The reaction was quenched with 1N NaOHsolution and the pH was adjusted to 10. The organic product wasextracted into 50 ml of CH₂Cl₂ and washed with water, then brine anddried over MgSO₄. Concentration gave the free amine (0.98 g; 98%) as ayellow syrup. TLC R_(f)=0.1 in 25% acetone/hexanes.Step 7: The product of step 6 (0.78 g; 2.21 mmol), DEC (0.65 g; 3.4mmol), HOBT (0.46 g; 3.4 mmol) and 2-amino-6-chloro benzoic acid (0.51g; 2.9 mmol) were dissolved in 8 ml of CH₂Cl₂ to which was addeddiisopropylethyl amine (0.7 ml) and the mixture was stirred at ambienttemperature for 16 h. TLC analysis showed absence of starting materialand formation of two over-lapping spots of medium polarity (rotomers ofthe hindered amide) as the major product. The crude product (1.3 g) wasisolated by extractive work up and purified through FSGC using 25%acetone in CH₂Cl₂ as eluant to give the title compound (0.88 g; 80%) asa pale yellow foam. TLC R_(f)=0.45 and 0.5 in 25% acetone:CH₂Cl₂.

A solution of hydrogen chloride in Et₂O (1M; 3 ml) was added to asolution of the title compound free base (0.76 g; 1.54 mmol) in CH₂Cl₂(5 ml) to obtain an instantaneous white precipitate. After stirring atRT for 2 h, the volatiles were removed on a rotary evaporator and thewhite residue was suspended in dry toluene (3×10 ml) and azeotroped. Thewhite solid thus obtained was suspended in dry Et₂O containing 10%EtOAc, stirred for 30 min, filtered and washed with Et₂O (100 ml). TheHCl salt of the title compound was dried under high vacuum to yield anoff-white solid (0.88 g; 95%). Mp: 205-210° C.

The product of step 6 was converted to other amides (4A-4E) as describedin step 7 using the appropriate carboxylic acids. Physical data forcompounds 4-4E having the following structures is as follows:

wherein R⁸ and R² are as defined in the table: Ex. R⁸ R² Mp (° C.) HRMS(MH⁺) 4 CF₃

205-210 509.2295 4A CF₃

192-195 489.2841 4B CF₃

203-206 490.2681 4C CF₃

186-190 488.2902 4D CF₃

207-210 489.2851 4E CF₃

152 505 4F CF₃

— 490.2796

EXAMPLE 5

A solution of the racemic benzyl chloride 24 (1.26 g, 5.62 mmol) whichwas prepared freshly from the corresponding carbinol, the 2(S)-methylpiperazine (1.12 g, 5.62 mmol) and 2,2,6,6-tetramethyl piperidine (TMP)(1.9 ml, 11.2 mmol) were dissolved in dry DMF (2 ml) and heated to100-110° C. (internal temp.) for 10 h. TLC analysis showed absence of 24and formation of two well-separated products. The mixture was dilutedwith water and the organics were extracted into Et₂O. The organicextract was washed with saturated NH₄Cl and brine and concentrated invacuo to obtain 2 g of crude product. Flash chromatography on silica geland elution first with 25% Et₂O-hexane followed by 25% EtOAc-hexane gave˜0.5 grams of 25a and ˜0.5 grams of 25b respectively (−45% combinedyield). TLC R_(f)=0.6 (for 25a) and 0.4 (for 25b) in 25% EtOAc-hexanes.Purified 25a was treated as described previously to obtain the finalproducts 5 to 5F having the formula.

wherein R² is as defined in the table: Ex. R² mp (° C.) HRMS 5

208-212 519.2958 5A

198-203 535.2913 5B

233 (sharp) 539.2390 5C

190 575.1800 5D

253 558.1887 5E

202 519.2964 5F

190 535.2901 5G

198-203 — 5H

205-210 —

EXAMPLE 6

Step 1:

A mixture of the aldehyde 26 (3.9 g, 20.5 mmol), the2(S)-methyl-N-BOC-piperazine (4.1 g, 20.5 mmol) and Ti(OiPr)₄ (6.1 mL;20.5 mmol) in 40 ml of CH₂Cl₂ was stirred at RT for 24 h. Et₂AlCN wasintroduced and stirred for an additonal day. The reaction mixture wasprocessed as described before to obtain 4.71 grams (58%) of the cyanoamine 27 after FSGC (TLC R_(f)=0.45/0.5 for diastereomers seen with 25%Et₂O-hexanes as solvent).

Step 2: Sodium hexamethyldisilazide (1M; 3.1 ml) was added to a solutionof 27 (1 g; 2.5 mmol) in dry THF cooled in a dry ice/acetone bath. Theresulting bright yellow solution was treated with CH₃CH₂₁ (7.5 mmol; 0.6ml). The dry ice bath was removed and the reaction was stirred atambient temperature for 15 min. followed by gentle warming in a warmwater bath (40° C.) for 30 min. TLC indicated two well-separated spots.Standard extractive work up and purification by FSGC gave two alkylatedcompounds (combined yield: 0.7 g; 70%). TLC R_(f)=0.6 and 0.4 (25%EtOAc/hexanes).

Step 3: The product of step 2 was stirred with NaBH(OAc)₃ (2×) andMgBr₂:OEt₂ (1×) in CH₃CN for a day. The reaction mixture was quenchedwith water, the organics were extracted into EtOAc and processed toobtain 0.8 grams of crude product. FSGC (25% EtOAc-hexanes) gave ˜0.4grams of each diastereomer (combined yield ˜100%). TLC R_(f)=0.55 (28a)and 0.45 (28b) in 25% EtOAc-hexanes.

Step 4: Compound 28a (S,S-diastereomer) was processed through the usual5 step sequence to complete the synthesis of compounds of Example 6, 6Aand 6B with an ipso-methyl group as well as compounds 6C and 6D whichlack the ipso-methyl group:

Ex. R⁶ R² mp (° C.) MS (MH⁺) 6 CH₃

204 549.5 6A CH₃

253 589.4 6B CH₃

260 534.4 6C H

225 520.4 6D H

215 575.4

EXAMPLE 7

The synthesis of compounds with an alkyl or arylsulfonyl R⁸ group at thepara position started with the corresponding para-substitutedacetophenone which was treated as in Example 4, steps 1-6 to obtain thesulfone containing compounds of Example 7 havng the formula:

wherein R⁸ and R² are as defined in the table: Ex. R⁸ R² Mp (° C.) HRMS(MH⁺) 7 H₃CSO₂—

220-225 498.2790 7A H₃CSO₂—

212-215 519.2197 7B

190 (dec.) 604.2861 7C

178 (dec.) 625.2246 7D

170 (dec.) 605.2799 7E

170 (dec.) 609.2540 7F

200 (dec.) 612.2336 7G

158 (dec.) 644.1735 7H H₃CSO₂—

197 (dec.) 514.2847

EXAMPLE 8

Step 1: A solution of the product of Example 4, step 4 (1.25 g; 4.6mmol), N-BOC-4-piperidinone (0.91 g; 4.6 mmol) and (Ti(OiPr)₄) (1.4 ml;4.6 mmol) in 10 ml of CH₂Cl₂ was stirred at ambient temperature for 24h. The reaction mixture was then treated with Et₂AlCN (5.5 ml; 1Msolution in toluene) and stirring continued for 20 h. The reactionmixture was diluted with EtOAc and stirred with saturated NaHCO₃solution (10 min.) and the layers were separated as much as possible.The turbid (from inseparable aqueous layer) organic layer was treatedwith excess celite and filtered, washing the filtercake with EtOAc. Thefiltrate layers were separated and the organic layer was washed withwater and brine, dried over anhydrous MgSO₄ and concentrated to obtain2.16 g (98%) of an amber gum.Step 2: The Strecker amine from step 1 (2.16 g) was dissolved in dryTHF, cooled in an ice bath and treated with CH₃MgBr (7.5 ml of a 3Msolution in Et₂O). After 1 h, the ice bath was removed and the yellow,heterogeneous reaction mixture was stirred at RT for 18 h. The reactionwas quenched with saturated NH₄Cl solution, diluted with water andextracted with CH₂Cl₂. Concentration gave 2.2 g of a yellow gum whichwas purified by FSGC, eluting the major product away from more polarimpurities using a 1:1 mixture of CH₂Cl₂:EtOAc. The ipso-methyl compoundwas isolated as a yellow gum (1.85 g; 88%). TLC R_(f)=0.5 in 1:1Et₂O:hexanes.Step 3: TFA (6 ml) was added to a solution of the product of step 2 (1.5g; 3.2 mmol) in 10 ml of CH₂Cl₂ and stirred at 25° C. for 2 h. Thereaction was quenched with 1N NaOH solution to a pH of 9-10 andprocessed by extraction into CH₂Cl₂ to obtain 1.2 g of crude product.FSGC using 1:1 CH₂Cl₂:EtOAc removed all the less polar impurities andgradient elution with 10% CH₃OH in CH₂Cl₂ and finally with 10% (ca.7N—NH₃) CH₃OH in CH₂Cl₂ led to the isolation of the free piperidine as ayellow gum (1.07 g; 90%). TLC R_(f)=0.2 in 10% CH₃OH:CH₂Cl₂.Step 4: A solution of the product of step 3 (1.03 g; 2.8 mmol),2,4-dimethyl nicotinic acid (0.42 g; 2.8 mmol), DEC (0.8 g; 4.2 mmol),HOBT (0.57 g; 4.2 mmol) and diisopropyl ethyl amine (1 ml; 5.6 mmol) inCH₂Cl₂ (15 ml) was stirred at 25° C. for 24 h. The reaction mixture wasdiluted with CH₂Cl₂ (25 ml), washed with water, 10% NaHCO₃ solution andbrine, then concentrated to obtain 1.6 g of crude oil. FSGC of thismaterial using gradient elution with 10% acetone-CH₂Cl₂ followed by 2-5%CH₃OH in CH₂Cl₂ gave the title compound (1.1 g; 80%) as a white foam.TLC R_(f)=0.45 in 5% CH₃OH—CH₂Cl₂.

The free base of the title compound (1 g; 2 mmol) isolated above wasdissolved in a 1:1 mixture of EtOAc:Et₂O (8 ml) and a fresh solution ofhydrogen chloride in Et₂O (6.1 ml of a 1M solution) was added, instantlyforming a white precipitate. After stirring at 25° C. for 1 h, thevolatiles were removed in vacuo. The product was suspended in Et₂O andfiltered, washing the filtrate with Et₂O. The HCl salt of the titlecompound thus obtained was dried in vacuo (1.1 g; mp. 213-215° C.). HRMS(MH⁺) 503.2997.

The following amides 8A-8E were prepared in a similar manner from theproduct of step 3 using appropriate acids, and compounds 8F-8H, whereinthe R⁸-substituent is a p-methyl sulfonyl group were similarly prepared.

wherein R⁸ and R² are as defined in the table: Ex. R⁸ R² Mp (° C.) HRMS(MH⁺) 8A CF₃

216 503.3021 8B CF₃

222-224 504.2850 8C CF₃

262-263 502.3039 8D CF₃

216-218 523.2466 8E CF₃

210-212 519.2970 8F —SO₂CH₃

201-205 512.2955 8G —SO₂CH₃

217-221 533.2355 8H —SO₂CH₃

216-219 514.2736 8I —CF₃

195-198 — 8J —CF₃

250-255 528.1791 8K —CF₃

223-226 576.1562 8L —CF₃

>245 528.2439 8M —CF₃

176-181 570.1739 8N —CF₃

218-223 708.0040 8O —CF₃

215-220 522.2507 8P —CF₃

208-212 566.1987 8Q —CF₃

190-194 586.1442 8R —CF₃

255-257 526.2243

Using procedures described following the table, compounds 8S-8EE of thestructure

were prepared, wherein R¹¹ is defined in the table: HRMS Ex. R¹¹ Mp (°C.) (MH⁺) 8S —OH 210-220 518.2997 (2 × HCl salt) 8T —OC(O)NHCH₂CH₃205-210 589.3374 (2 × HCl salt) 8U —OSO₂CH₃ 165-171 596.2757 (2 × HClsalt) 8V

199-204 (2 × HCl salt) 595.3254 8W —CHO 88-92 530.2985 8X —CH═NH—OCH₃202-205 559.3260 (2 × HCl salt) 8Y —CHF₂ >245 (dec) 552.3020 (2 × HClsalt) 8Z —NH—C(O)—NH—CH₂CH₃ 214-219 588.3521 (2 × HCl salt) 8AA —NH₂92-98 517.3154 8BB —NHSO₂CH₂CH₃ 205-211 609.3078 (2 × HCl salt) 8CC —F212-217 520.2949 (2 × HCl salt) 8DD —Cl 235-238 536.2663 (2 × HCl salt)8EE —Br 237-240 580.2141 (2 × HCl salt)8S: The tri-hydrochloride salt of the product of Example 8, step 3 (75mg, 0.16 mmol), EDC (61 mg, 0.32 mmol), HOBT (49 mg, 0.32 mmol), iPr₂NEt(0.16 ml, 0.96 mmol), and 2,6-dimethyl-4-hydroxy-benzoic acid (53 mg,0.32 mmol) were taken up in CH₂Cl₂ and stirred at 25° C. for 20 h. Thesolution was concentrated. Purification via preparative TLC (EtOAc,SiO₂) gave the title compound as a yellow oil. m.p. (2×HCl salt)210-220° C. HRMS (MH⁺) calcd. for C₂₉H₃₉O₂N₃F₃, 518.2994; Found,518.2997.8T: 8S (100 mg, 0.19 mmol), ethyl isocyanate (0.05 ml, 0.58 mmol), andEt₃N (0.13 ml, 0.95 mmol) were taken up in CH₂Cl₂ and stirred at 25° C.for 16 h. The solution was diluted with CH₂Cl₂ and washed with 1 N NaOH.The organic layer was dried (Na₂SO₄), filtered, and concentrated.Purification via preparative TLC (2/1 EtOAc/hexanes, SiO₂) gave thetitle compound as a yellow oil.8U: 8S (250 mg, 0.48 mmol), methane sulfonyl anhydride (250 mg, 1.44mmol), and NaH (38 mg, 60 wt % in oil) were taken up in THF and stirredat 25° C. for 20 h. The solution was diluted with EtOAc and washed withsat'd NaHCO₃. The organic layer was dried (Na₂SO₄), filtered, andconcentrated. Purification via preparative TLC (1/1 EtOAc/hexanes, SiO₂)gave the title compound as a yellow oil (280 mg, 98%).8V: The tri-hydrochloride salt of the product of Example 8, step 3 (50mg, 0.1 mmol), EDC (38 mg, 0.2 mmol), HOBT (27 mg, 0.2 mmol), iPr₂NEt(0.07 ml, 0.4 mmol), and 2,6-dimethyl-4-(4-pyridyl-N-oxide)-benzoic acid(73 mg, 0.3 mmol) (see preparation below) were taken up in CH₂Cl₂ andstirred at 25° C. for 19 h. The solution was concentrated. Purificationvia preparative TLC (2/1 acetone/hexanes, SiO₂) gave 8V as a yellow oil(23 mg, 39%).

Preparation of 2,6-dimethyl-4-(4-pyridyl-N-oxide) benzoic acid

Step A: 4-Benzyloxy-2,6-dimethyl benzoic acid (8.7 g, 34 mmol; Thea, S.et al Journal of the American Chemical Society 1985, 50, 1867), MeI (3.2ml, 51 mmol), and Cs₂CO₃ (17 g, 51 mmol) were allowed to stir in DMF at25° C. for 17 h. The solution was filtered and partitioned between Et₂Oand water. The aqueous layer was extracted with Et₂O. The combined Et₂Olayers were washed with H₂O and brine. The organic layer was dried(MgSO₄), filtered, and concentrated. Purification via flashchromatography (10/1 hexanes/Et₂O, SiO₂) gave 8.6 g (94%) of the methylester as a colorless oil.Step B: The benzyl protected phenol (8.5 g, 32 mmol) and Pd/C (750 mg,10 wt % Pd) were taken up in CH₃OH. The solution was charged with 50 psiH₂ and shaken in a Parr apparatus at 25° C. for 17 h. The solution wasfiltered (Celite). Concentration gave 5.6 g (98%) of the phenol as awhite solid.Step C: The phenol (3.5 g, 19.4 mmol) and iPr₂NEt (3.76 g, 29.1 mmol)were dissolved in CH₂Cl₂ at 0° C. Triflic anhydride (Tf₂O) (4.2 ml, 25.2mmol) was added dropwise to the solution at 0° C. The solution waswarmed to 25° C. and stirred at that temperature for 4.5 h. The solutionwas diluted with CH₂Cl₂ and washed with sat NaHCO₃. The aqueous layerwas extracted with CH₂Cl₂. The combined organic layers were dried overNa₂SO₄. Filtration and concentration gave the crude aryl triflate.Purification via flash chromatography (10/1, hexanes/Et₂O, SIO₂) gave5.7 g (94%) of the triflate as a yellow oil.Step D: The triflate (1 g, 3.2 mmol), 4-pyridyl boronic acid (1.2 g, 9.6mmol), Pd(PPh₃)₄ (370 mg, 0.32 mmol), and Na₂CO₃ (1 g, 9.6 mmol) weretaken up in DME/H₂O (4/1, 25 ml). The solution was heated to 90° C. (oilbath) under N₂ for 18 h. The solution was partitioned between EtOAc andH₂O. The aqueous layer was extracted with EtOAc. The combined EtOAclayers were dried (Na₂SO₄). Filtration and concentration gave a darkbrown oil. Purification via flash chromatography (3/1 hexanes/EtOAc,SiO₂) gave 770 mg (100%) of the pyridyl derivative as an orange oil.Step E: The pyridyl derivative (390 mg, 1.6 mmol) and mCPBA (550 mg, 3.2mmol) were dissolved in CH₂Cl₂. The solution was stirred at 25° C. for18 h. The solution was diluted with CH₂Cl₂ and washed with 1 N NaOH. Theorganic layer was dried (Na₂SO₄). Filtration and concentration gave 400mg (97%) of the N-oxide as an orange oil. HRMS (MH⁺) calcd. forC₁₅H₁₆O₃N, 258.1130; Found, 258.1131.Step F: The methyl ester (400 mg, 1.6 mmol) was taken up in 5 ml of 3 NNaOH and 2 ml of EtOH. The solution was heated at reflux for 20 h. Thesolution was concentrated. The residue was treated with conc. HCl. Theresulting solid was filtered and washed with water and brine. Afterdrying under high vacuum, the free acid (377 mg, 100%) was obtained as atan solid. m.p.>225° C. (decomp). HRMS (MH⁺) calcd. for C₁₄H₁₄O₃N,244.0974; Found, 244.0981.8W: The tri-hydrochloride salt of the product of Example 8, step 3 (1.34g, 2.8 mmol), 2,6-dimethyl-4-formyl benzoic acid (500 mg, 2.8 mmol) (seepreparation below), EDC (1.1 g, 5.6 mmol), HOBT (760 mg, 5.6 mmol) andiPrNEt (2 ml, 11 mmol) were subjected to the standard couplingconditions. Purification via flash chromatography (2/1 hexanes/EtOAc,SiO₂) gave 898 mg (61%) of 8W as a yellow foam.

Preparation of 2,6-dimethyl-4-formyl benzoic acid

Step A: 4-Hydroxy-2,6-dimethyl-benzoic acid, tert-butyl ester (6.4 g, 29mmol) and iPr₂NEt (5.6 g, 43 mmol) were taken up in CH₂Cl₂ and cooled to0° C. Tf₂O (5.8 ml, 34 mmol) was added slowly to the solution at 0° C.The solution was stirred at 0° C. for 3 h. The solution was partitionedbetween sat. NaHCO₃ and CH₂Cl₂. The aqueous layer was extracted withCH₂Cl₂. The combined organic layers were dried (Na₂SO₄). Filtration andconcentration gave a brown oil. Purification via flash chromatography(20/1 hexanes/Et₂O, SiO₂) gave 7.99 g (82%) of the triflate as a yellowsolid.Step B: The triflate (5 g, 15 mmol), LiCl (1.25 g, 30 mmol), Pd(PPh₃)₄(340 mg, 0.3 mmol), and vinyl tributyl tin (4.5 ml, 16 mmol) were takenup in THF under N₂. The solution was heated at 70° C. for 16 h. Thesolution was partitioned between EtOAc and sat. KF. The mixture wasfiltered. The organic layer was separated, and the aqueous layers wereextracted with EtOAc. The combined organic layers were dried (MgSO₄).Filtration and concentration gave a yellow oil. Purification via flashchromatography (20/1 hexanes/Et₂O, SiO₂) gave 1.96 g (57%) of the olefinas a yellow oil.Step C: The olefin (0.6 g, 2.6 mmol) was taken up in CH₂Cl₂/MeOH (1/1).The solution was cooled to −78° C. Ozone was bubbled through thesolution until a dark blue color persisted. The reaction was quenchedwith dimethyl sulfide. The reaction was concentrated to furnish thealdehyde as an oil.Step D: The tert-butyl ester (650 mg, 2.8 mmol) and TFA (3 ml) weretaken up in CH₂Cl₂ and stirred at 25° C. for 19 h. Concentration of thesolution gave the acid as a beige solid.8X: 8W (100 mg, 0.19 mmol), H₂NOMe-HCl (28 mg, 0.34 mmol), NaOAc (32 mg,0.46 mmol) were taken up in MeOH. The solution was stirred at 25° C. for17 h. The solution was concentrated. The residue was partitioned betweenCH₂Cl₂ and 1 N NaOH. The aqueous layer was extracted with CH₂Cl₂. Thecombined organic layers were dried (Na₂SO₄). Filtration andconcentration gave the crude product. Purification via preparative TLC(1/1 hexanes/EtOAc, SiO₂) gave 85 mg (84%) of 8×.8Y: The tri-hydrochloride salt of the product of Example 8, step 3 (75mg, 0.16 mmol) and 4-difluoromethyl-2,6-dimethyl benzoic acid (32 mg,0.16 mmol) were subjected to the standard coupling conditions(EDC/HOBT/iPr₂NEt). Purification via preparative TLC (2/1 hexanes/EtOAc,SiO₂) gave 64 mg (73%) of 8Y.

Preparation of 4-difluoromethyl-2,6-dimethyl benzoic acid

Step A: The aldehyde (400 mg, 1.7 mmol),[bis(2-methoxyethyl)amino]-sulfur trifluoride (640 mg, 2.9 mmol), andEtOH (0.02 ml, 0.34 mmol) were taken up 1,2-dichloroethane and stirredat 65° C. for 6 h and at 25° C. for 19 h. The solution was quenched withsat. NaHCO₃. The aqueous layer was extracted with CH₂Cl₂. The combinedorganic layers were dried (NaSO₂). Filtration and concentration gave thecrude product. Purification via preparative TLC (10/1 hexanes/Et₂O,SiO₂) gave 210 mg (50%) of the difluoro derivative.Step B: The tert-butyl ester (210 mg, 0.82 mmol) and HCl (2.1 ml of 4 Min dioxane, 8.2 mmol) were taken up in MeOH. The solution was stirred at45° C. for 20 h. The solution was concentrated to obtain the acid as awhite solid.8Z: The tri-hydrochloride salt of the product of Example 8, step 3 (811mg, 1.7 mmol) and 4-[(ethylamino)carbonylamino]-2,6-dimethyl benzoicacid (400 mg, 1.7 mmol) (see preparation below) were subjected to thestandard coupling conditions (EDC/HOBT/iPr₂NEt). Purification via flashchromatography (1/1 hexanes/acetone, SiO₂) gave 803 mg (81%) of 8Z as afoam.

Preparation of 4-[(ethylamino)carbonylamino]-2,6-dimethyl benzoic acid

Step A: 3,5-Dimethyl aniline (18.5 ml, 149 mmol) was taken up in CH₂Cl₂.The solution was cooled in a water bath. Trifluoroacetic anhydride (29.5ml, 209 mmol) was added slowly to the solution. After the addition, thesolution was stirred at 25° C. for 15 minutes. Bromine (7.3 ml, 142mmol) was added slowly to the solution while maintaining the RT waterbath. The solution was stirred at 25° C. for 3.5 h. The solution wasquenched with 10% Na₂S₂O₃. The aqueous layer was extracted with CH₂Cl₂.The combined organic layers were dried (MgSO₄), treated with activatedcarbon and filtered. Concentration gave an orange solid. Purificationvia recrystallization (hexanes/Et₂O) gave two crops (34 g total, 77%) ofthe brominated derivative as a white solid.Step B: The aryl bromide (17 g, 57 mmol) was taken up in THF and cooledto −78° C. under N₂. Methyllithium/LiBr (54 ml of a 1.5 M solution inEt₂O, 80 mmol) was added slowly to the solution at −78° C. After 5 minof stirring, sec-BuLi (62 ml of a 1.3 M in cyclohexane, 80 mmol) wasadded slowly to the reaction solution at −78° C. After 5 min, di-t-butyldicarbonate (22.5 g, 103 mmol) in THF was added to the solution at −78°C. The solution was warmed to 25° C. After 30 min, the reaction mixturewas partitioned between water and CH₂Cl₂. The aqueous layer wasextracted with CH₂Cl₂. The combined organic layers were dried (MgSO₄).Filtration and concentration gave a yellow solid. Purification via flashchromatography (1/1 to 1/4 hexanes/CH₂Cl₂, SiO₂) gave 13.1 g (72%) ofthe tert-butyl ester as an off-white solid.Step C: The trifluoro-acetamide (10 g, 31 mmol) and NaOH (2.5 g, 62mmol) were taken up in MeOH/H₂O (3/1) and heated at 60° C. for 3 h. Thesolution was partitioned between CH₂Cl₂ and water. The aqueous layer wasextracted with CH₂Cl₂. The combined organic layers were washed withwater and dried (Na₂SO₄). Filtration and concentration gave 6.4 g (93%)of the aniline as an orange solid.Step D: The aniline (1 g, 4.5 mmol), ethyl isocyanate (0.4 ml, 5 mmol),and CuCl (90 mg, 0.9 mmol) were taken up in DMF at 0° C. The solutionwas warmed to 25° C. and stirred at that temperature for 2 h. Thesolution was partitioned between EtOAc and 10% NH₄OH. The aqueous layerwas extracted with EtOAc. The combined layers were washed with brine anddried (MgSO₄). Filtration and concentration gave a yellow solid.Purification via flash chromatography (3/1 to 1/1 hexanes/EtOAc, SiO₂)gave 904 mg (69%) of the urea as a yellow solid.Step E: The tert-butyl ester (900 mg, 3.1 mmol) and 4 M HCl in dioxane(3 ml) were taken up in iPrOH and heated at 45° C. for 3.5 h and at 25°C. for 16.5 h. The solution was concentrated under reduced pressure. Theresidue was partitioned between Et₂O and 1 N NaOH. The aqueous, basiclayer was extracted with Et₂O. The aqueous layer was cooled to 0° C. andacidified with conc. HCl (pH=1-2). The aqueous layer was extracted withEtOAc. The combined EtOAc layers were dried (Na₂SO₄). Filtration andconcentration gave the 400 mg (55%) of the acid as a white solid.8AA: The tri-hydrochloride salt of the product of Example 8, step 3 (2g, 4.3 mmol) and 4-amino-2,6-dimethyl benzoic acid (710 mg, 4.3 mmol)(see preparation below) were subjected to the standard couplingconditions (EDC/HOBT/iPr₂NEt). Purification via flash chromatography(2/1 hexanes/acetone, SiO₂) gave 1.16 g (52%) of 8AA as a yellow foam.

Preparation of 4-amino-2,6-dimethyl benzoic acid

The tert-butyl ester (950 mg, 4.3 mmol) and HCl (11 ml, 4 M in dioxane)were taken up in MeOH at heated at 45° C. for 20 h. The solution wasconcentrated to obtain the acid (710 mg) in quantitative yield.

8BB: 8AA (100 mg, 0.19 mmol) and ethane sulfonyl chloride (0.02 ml, 0.21mmol) were taken up in pyridine and stirred at 25° C. for 19 h. Thesolution was concentrated. The residue was partitioned between 1 N NaOHand CH₂Cl₂. The aqueous layer was extracted with CH₂Cl₂. The combinedorganic layers were dried (Na₂SO₄). Filtration and concentration gave abrown oil. Purification via preparative TLC (2/1 hexanes/acetone, SIO₂)gave 100 mg (86%) of 8BB as a colorless oil.

8CC: The trihydrochloride salt of the product of Example 8, step 3 (127mg, 0.27 mmol) and 4-fluoro-2,6-dimethyl benzoic acid (58 mg, 0.35 mmol)(see preparation below) were coupled according to the general procedure(EDC/HOBT/iPr₂NEt). Purification via preparative TLC (2/1 hexanes/EtOAc,SiO₂) gave 8CC as a colorless oil (87 mg bis-HCl salt, 54%).

Preparation of 4-fluoro-2,6-dimethyl benzoic acid

4-Amino-2,6-dimethyl benzoic acid (200 mg, 1.1 mmol) and NOBF₄ (196 mg,1.7 mmol) were heated in 1,2-dichlorobenzene at 100° C. for 30 min. Thesolution was cooled and diluted with MeOH and water. A few pellets (2-3)of KOH were added, and the solution was heated at reflux for 16 h. Thesolution was concentrated. The residue was partitioned between Et₂O and1 N NaOH. The aqueous layer was extracted with Et₂O. The aqueous layerwas cooled to 0° C. and acidified with conc. HCl (pH=1-2). The aqueouslayer was extracted with CH₂Cl₂. The organic layers were dried (Na₂SO₄).Filtration and concentration gave 58 mg (31%) of the acid as a tansolid.

8DD: The trihydrochloride salt of the product of Example 8, step 3 (150mg, 0.31 mmol) and 4-chloro-2,6-dimethyl benzoic acid (76 mg, 0.41 mmol)(see preparation below) were coupled according to the general procedure(EDC/HOBT/iPr₂NEt). Purification via preparative TLC (4/1hexanes/acetone, SiO₂) gave 8DD as a colorless oil.

Preparation of 4-chloro-2,6-dimethyl benzoic acid

4-Amino-2,6-dimethyl benzoic acid (172 mg, 0.96 mmol) and CuCl₂ (155 mg,1.15 mmol) were taken up in CH₃CN at 0° C. Tert-butyl nitrite (0.17 ml,1.4 mmol) was added to the solution at 0° C. The solution was warmed to25° C. and then at 65° C. for 45 min. The solution was partitionedbetween Et₂O and water. The aqueous layer was extracted with Et₂O. Thecombined organic layers were washed with brine and dried (MgSO₄).Filtration and concentration gave the methyl ester. The methyl ester washydrolyzed as described above for the fluoro derivative (KOH). Afterextractive workup, 4-chloro-2,6-dimethyl benzoic acid (158 mg, 89%) wasobtained as a yellow solid.

8EE: The trihydrochloride salt of the product of Example 8, step 3 (180mg, 0.38 mmol) and 4-bromo-2,6-dimethyl benzoic acid (95 mg, 0.41 mmol)(see preparation below) were coupled according to the general procedure(EDC/HOBT/iPr₂NEt). Purification via preparative TLC (4/1hexanes/acetone, SiO₂) gave 8EE as a colorless oil (140 mg bis-HCl salt,56%).

Preparation of 4-bromo-2,6-dimethyl benzoic acid

Step A: The triflate (500 mg, 1.48 mmol), hexamethylditin (0.31 mmol,1.48 mmol), LiCl (377 mg, 8.9 mmol), and Pd(PPh₃)₄ (171 mg, 0.15 mmol)were heated in THF (70° C.) under N₂ for 21 h. The solution waspartitioned between Et₂O and pH=7 buffer (NH₄OAc). The aqueous layer wasextracted with Et₂O. The combined Et₂O layers were washed with brine anddried (Na₂SO₄). Filtration and concentration gave the crude arylstannane as a yellow semisolid.Step B: The aryl stannane (0.74 mmol) was taken up in CH₂Cl₂ at 0° C.Bromine (0.7 ml of 1 M Br₂ in CH₂Cl₂) was added to the solution. Thesolution was stirred at 0° C. for 30 min. The solution was diluted withCH₂Cl₂ and washed with 10% Na₂S₂O₃. The aqueous layer was extracted withCH₂Cl₂. The combined organic layers were dried (Na₂SO₄). The solutionwas filtered. TFA (2 ml) was added to the solution, and the solution wasstirred at 25° C. for 17 h. The solution was concentrated. The residuewas partitioned between Et₂O and 1 N NaOH. The aqueous layer wasextracted with Et₂O. The aqueous layer was cooled to 0° C. and acidifiedwith conc. HCl (pH=1-2). The aqueous layer was extracted with CH₂Cl₂.The combined organic layers were dried (Na₂SO₄). Filtration andconcentration gave 100 mg (59%) of the acid as a white solid.

Using procedures described following the table, compounds 8FF-8HH of thestructure

were prepared, wherein R¹¹ is defined in the table: Ex. R¹¹ Mp (° C.)HRMS (MH⁺) 8FF —OCH₃ 217-220 572.2048 (2×HCl salt) 8GG —OH 198-204558.1898 (2×HCl salt) 8HH

200-205 (2×HCl salt) 635.21728FF: The trihydrochloride salt of the product of Example 8, step 3 (100mg, 0.21 mmol) and 2,6-dichloro-4-methoxy-benzoic acid (140 mg, 0.63mmol) were coupled according to the general procedure(EDC/HOBT/iPr₂NEt). Purification via preparative TLC (3/1 hexanes/EtOAc,SiO₂) gave 8FF as a colorless oil (27 mg, 23%).8GG: The trihydrochloride salt of the product of Example 8, step 3 (330mg, 0.7 mmol) and 2,6-dichloro-4-hydroxy-benzoic acid (290 mg, 1.4 mmol)(see preparation below) were coupled according to the general procedure(EDC/HOBT/iPr₂NEt). Purification via preparative TLC (1/1 hexanes/EtOAc,SiO₂) gave 8GG as a colorless oil (75 mg, 19%).

Preparatiion of 2,6-dichloro-4-hydroxy-benzoic acid

2,6-Dichloro-4-methoxy-benzoic acid (500 mg, 2.3 mmol) was taken up inCH₂Cl₂ and cooled to −78° C. BBr₃ (6.9 ml of a 1 M solution in CH₂Cl₂)was added to the solution at −78° C. The solution was warmed to 25° C.and stirred at that temperature for 16 h. The solution was quenched with3 N NaOH. The aqueous layer was extracted with CH₂Cl₂. The aqueous layerwas cooled (0° C.) and acidified with conc. HCl (pH=1-2). The aqueouslayer was extracted with CH₂Cl₂. The combined organic layers were dried(Na₂SO₄). Filtration and concentration gave the crude phenol which wasused without further purification.

8HH: The trihydrochloride salt of the product of Example 8, step 3 (96mg, 0.2 mmol) and 2,6-dichloro-4-(4-pyridyl-N-oxide)-benzoic acid (55mg, 0.2 mmol) (see preparation below) were coupled according to thegeneral procedure (EDC/HOBT/iPr₂NEt). Purification via preparative TLC(1/5 hexanes/acetone, SiO₂) gave 8HH as a colorless oil (54 mg, 43%).

Preparation of 2,6-dichloro-4-(4-pyridyl-N-oxide) benzoic acid

2,4,6-Trichloro benzoic acid, tert-butyl ester (500 mg, 1.8 mmol),4-pyridyl boronic acid (270 mg, 2.16 mmol), Pd(PCy₃)₂Cl₂ (130 mg, 0.18mmol), and CsF (540 mg, 3.6 mmol) were taken up in NMP and heated at100° C. under N₂ (16 h). The solution was partitioned between EtOAc andwater. The aqueous layer was extracted with EtOAc. The combined organiclayers were washed with water and brine and dried (Na₂SO₄). Filtrationand concentration gave the crude product. Purification via preparativeTLC (1/1 hexanes/EtOAc, SiO₂) gave 68 mg (12%) of the pyridyl ester. Thetert-butyl ester was converted into the acid as done previously for thedimethyl derivative (a. mCPBA/b. TFA).

Using suitable starting materials and the procedures described forexamples 8S to 8HH, the compounds of the following structure wereprepared:

wherein R¹¹ is defined in the table HRMS (MH⁺) HRMS (MH⁺) Ex. R¹¹ m.p.(° C.) calc. found 8II —OCH₃ 236-240 532.3151 532.3166 8JJ —CH₃ >260516.3202 516.3213 8KK

186-190 603.3522 603.3513 8LL

202-208 579.3311 579.3303 8MM

210-216 579.3311 579.3311 8NN

196-203 595.3260 595.3256 8OO

>230 (dec) 578.3358 578.3368 8PP

135-140 617.3679 617.3671 8QQ

205-215 602.3682 602.3722 8RR CH₂OH >235 (dec) 532.3151 532.3124 8SS

206-212 580.3263 580.3258 8TT

198-204 579.3311 579.3315 8UU

231-236 580.3263 580.3252 8VV

201-207 613.2977 613.2981 8WW

215-220 650.2487 650.2497 8XX

198-201 545.3103 545.3098 8YY

210-214 595.2930 595..2921 8ZZ CH₂F >245 534.3108 534.3117 8AB

202-205 624.3195 624.3204 8AC

208-213 559.3260 559.3263 8AD

215-220 560.3212 560.3220 8AE

215-220 573.3416 573.3424 8AF

215-220 559.3260 559.3257 8AG

205-209 602.3682 602.3672 8AH

186-192 574.3389 574.3378 8AI

200-206 616.3838 616.3844 8AJ

165-173 661.3941 661.3949 8AK CN 240-250 527.2998 527.2991 8AL

211-215 622.3136 622.3129 8AM

170-174 616.3838 616.3836 8AN

192-196 614.3682 614.3690All melting points were done on the bis hydrochloride salts (2×HCl)except 8PP was performed on the free base

Using derivatives of the triflate intermediate described in 8Z inprocedures similar to those described above and following the table for8AO-8AQ, the compounds of the following structure were prepared:

wherein R¹¹ is defined in the table Ex. R¹¹ m.p. (° C.) 8AO —CN 240-2508AP —CONHEt 215-220 8AQ -N(CH₃)CONHEt 186-203 8AR —CONH₂ 200-208 8AS—CONHCH₃ 215-220 8AT —CON(CH₂CH₂OCH₃)₂ 165-173 8AU —CON(Et)₂ 170-180 8AV—N(CH₃)CONHCH₃ 198-210 8AW —NHCH₃ 190-200 8AX —N(CH₃)CONH₂ 190-220 8AO:

Step 1: The triflate intermediate (see 8W) (0.4 g), Zn(CN)₂ (0.2 g),Pd(PPh₃)₄ (0.3 g) and DMF (1.5 ml) were heated at 80° C. for 17 h. Thereaction was cooled to RT, diluted with EtOAc and saturated aqueousNaHCO₃. The EtOAc layer was removed, washed with water, dried with brineand evaporated to give a crude oil which was purified by preparativeplate chromatography (2000 μM silica plates; 8:1 hexanes: EtOAc eluant),to give, after isolation of the appropriate band, the cyano intermediate(0.2 g) in 77% yield.Step 2: The product of Step 1 (0.2 g) was dissolved in MeOH (1.5 ml) andHCl (4M solution in 1,4-dioxane; 2 ml) was added. The resulting solutionwas stirred at 50° C. for 3 h and evaporated. This crude intermediate(0.038 g) and the product of Example 8, Step 3 (65 mg; trihydrochlorideform) were treated in the same fashion as Example 8, Step 4, using DMF(2 ml), HOBt (45 mg), DEC (60 mg) and diisopropyl ethyl amine (0.1 ml)to give, after isolation and purification, the free base form of 8AO,which was converted to its HCl salt (45 mg) in 95% yield.

Step 1: 2,6-Dimethyl-4-formyl benzoic acid (1.96 g) (see 8W) wasdissolved in t-butanol (94 ml) and 2-methyl-2-butene (24 ml). A solutionof NaClO₂ (6.89 g), NaH₂PO₄ monohydrate (8.17 g) and water (45 ml) wasadded dropwise to the first solution. After complete addition, the pHwas adjusted to 3 and two layers resulted. The organic layer was removedand evaporated to give intermediate acid (1.80 g) as a white crystallinesolid, which was used without purification.Step 2: To a solution of the product of Step 1 (0.62 g), CH₂Cl₂ (5 ml)and DMF (1 drop) was added oxalyl chloride (0.31 ml) and the resultingsolution was stirred for 10 min, at which time a second portion ofoxalyl chloride (0.30 ml) was added. The reaction was stirred for 10min, toluene was added and the mixture was evaporated to dryness. CH₂Cl₂(10 ml) and EtNH₂ (1 ml) were added and the reaction was stirred for 2days, then partitioned between brine and CH₂Cl₂. The CH₂Cl₂ layer wasevaporated and HCl (4 ml of a 4 M solution in 1,4-dioxane) was added.The resulting solution was stirred for 3 h and evaporated to give asolid which was washed with Et₂O and collected to give the amideintermediate (0.13 g) in 24% yield.Step 3: The product of Example 8, Step 3 (60 mg; trihydrochloride form)and the product of step 2 (35 mg) were treated in the same fashion asExample 8, Step 4 to give, after work up and purification, 8AP as thefree base form, which was converted to the HCl salt (50 mg) in 62%yield.

Step 1: To a solution of the amine intermediate (2 g) (see 8Z) was addedNaH (0.4 g of a 60% oil dispersion). The resulting suspension wasstirred for 15 min and Me₂SO₄ was added. After heating at reflux for 1.5h, the reaction was cooled to RT, poured into saturated NH₄Cl aqueoussolution and extracted with Et₂O. After evaporation, the crude reactionmixture was chromatographed on silica gel, eluting with 4:1hexanes:EtOAc, to give, after evaporation of the appropriate fractions,the methylamine intermediate (0.8 g) in 38% yield.Step 2: The product of Step 1 (0.12 g), THF (5 ml) and EtNCO (54 mg)were heated at reflux for 17 h. EtNCO (54 mg) and 1,4-dioxane (2 ml)were added and the resulting solution was heated in a sealed tube at 65°C. for 17 h. The solution was cooled, evaporated and purified bypreparative plate chromatography (silica gel; 25% EtOAc:CH₂Cl₂), to givethe desired product (0.1 g) as a crystalline solid in 64% yield.Step 3: The product of Step 2 (0.1 g) was treated in the same fashion asExample 8, Step 3 (p 28) to give the desired intermediate (0.08 g) whichwas used directly in the next step.Step 4: The product of Example 8, Step 3(75 mg; trihydrochloride form)and the product of Step 3 (0.04 g) were treated in the same fashion asExample 8, Step 4, to give, after work up and purification, 8AQ as thefree base form, which was converted to the HCl salt (65 mg) in 62%yield.

Using procedures described above and employing commercially availableacids, compounds 8AY-8BT of the structure

were prepared, wherein R¹⁰ and R¹¹ are defined in the table: Ex. R¹⁰ R¹¹Mp (° C.) 8AY —CH₃ H 205-208 8AZ F H 250-255 8BA Cl H 215-217 8BC —CH₃Br 228-231 8BD —CH₃

194-198 8BE Cl Cl 240-241 8BF Cl F 268-270 8BG Br H 210-213 8BH Cl Br213-217 8BI Br F 176-181 8BJ I H 184-190 8BK —CF₃ F 204-209 8BL F F268-270 8BM Cl NH₂ 215-220 8BN H F 258-260 8BO H Br 238-240 8BP H Cl235-240 8BQ Br Cl 190-194 8BR CH₃CH₂— H 211-214 8BS —Si(CH₃)₃ H 230-2408BT Cl NO₂ 275-280

Using procedures similar to those described above, the followingcompounds were prepared:

wherein R⁸, R³, R⁶ and R² are as defined in the table: Ex. R⁸ R³ R⁶ R²Mp (° C.) 8BU —CF₃

—CH₃

195-220 8BV —CF₃

—CH₃

80-85 8BW —CF₃

—CH₃

212-217 8BX —CF₃

—CH₃

235-238 8BY —CF₃

—CH₃

195-200 8BZ —CF₃

—CH₃

237-240 8CA —CF₃

—CH₂CH₃

179-181 8CB —CF₃

—CH₂CH₃

200-202 8CD —CF₃

—CH₂CH₃

199-205 8CE

—CH₃

206-210 8CF —CF₃

—CH₃

235-239

EXAMPLE 9

Step 1: A solution of 4-N-BOC-2(S)-methyl piperazine (1.5 g; 7.5 mmol),4-methoxy-benzyl chloride (1.1 ml; 8.1 mmol) and diisopropyl ethyl amine(1.5 ml) in dry CH₃CN were heated at reflux for 5 h. The reactionmixture was cooled to RT and volatiles were removed in vacuo. Theresidue was dissolved in CH₂Cl₂ (30 ml) and washed with water and brine.Concentration gave the crude product, which was purified by FSGC (10%EtOAc-hexanes) to obtain 2.1 g (88%) of product as a pale yellow liquid.

TFA (6 ml) was added to a solution of the above compound (2.1 g; 6.56mmol) in 12 ml of CH₂Cl₂ and the mixture stirred at 25° C. for 1.5 h.The reaction was quenched with 1 N NaOH and adjusted to pH 10.Extractive work-up in CH₂Cl₂ furnished the desired product (1.4 g; 97%)as a colorless gum.

Step 2: A mixture of the product of step 1 (1.4 g; 6.36 mmol),N-BOC-4-piperidinone (1.27 g; 6.4 mmol) and Ti(OiPr)₄ (1.9 ml; 6.4 mmol)was stirred at 25° C. for 24 h. A 1M solution of Et₂AlCN in toluene (7.6ml) was added to the reaction mixture and the mixture stirred at ambienttemperature for another day. The Strecker amine thus formed wasworked-up and isolated (2.7 g; 100%) as described in Example 8, step 2.TLC R_(f)=0.3 in 25% EtOAc—CH₂Cl₂.

The Strecker amine (2.7 g; 6.3 mmol) was dissolved in 15 ml of dry THFat 0° C. and CH₃MgBr (3M in Et₂O; 10.5 ml) was added to it. After 1 h,the ice bath was removed and the reaction allowed to proceed at RT for15 h. TLC analysis of the heterogeneous reaction mixture showed nochange from the starting material; the mixture was warmed at 60° C. for5 h with no observed change in TLC behavior. The reaction mixture wasquenched with saturated NH₄Cl and organic products extracted intoCH₂Cl₂. FSGC of the crude product (2.7 g) using 15% acetone-hexanes asthe eluant provided the desired ipso-methyl compound as a colorless gum(2.3 g; 87%).

Step 3: The product of step 2 (1.7 g; 4.08 mmol), ammonium formate (1.4g; 22 mmol) and 10% palladium on carbon (0.4 g) were mixed in 20 ml ofCH₃OH and heated at reflux for 5 h. The reaction mixture was filteredthrough celite and volatiles were removed. The residue was dissolved inCH₂Cl₂ and washed with 10% NaOH solution, water and brine. Concentrationin vacuo gave 1.1 g (92%) of pale yellow gum.

Step 4: A solution of the product of step 3 (0.12 g; 0.4 mmol),p-trifluoro-methyl benzyl bromide (0.1 g; 0.4 mmol) and diisopropylethyl amine (0.1 ml) in dry CH₃CN was gently warmed (60-70° C.) for 16h. The mixture was cooled and organic product isolated via extractivework-up in CH₂Cl₂. FSGC (10-30% Et₂O—CH₂Cl₂; R_(f)=0.4) yielded themajor product as a colorless film (0.12 g; 68%).

Treatment of the above product (in CH₂Cl₂) with TFA (1 ml) for 1 hfollowed by basification and standard work-up provided the desiredcompound (0.09 g; 96%) as a colorless film.

Step 5: The product of step 4 (0.045 g; 0.13 mmol) and 6-chloroanthranilic acid (0.022 g; 0.13 mmol) were coupled as described inExample 1 and after work-up and FSGC (5% CH₃OH in CH₂Cl₂) the titlecompound was isolated as a colorless film (0.058 g; 90%).

The HCl salt of the title compound was prepared in the usual manner bythe reaction of the free base with 1M HCl-Et₂O and processing theprecipitate to obtain a beige solid (0.066 g).

Using a similar procedure, the product of step 3 was converted to othercompounds, first by alkylation of the piperazine nitrogen with theappropriate halide, followed by deprotection and coupling of thepiperidinyl portion with the appropriate acid to form the amides ofgeneral structure:

wherein R and R² are as defined in the table: HRMS Ex. R R² Mp (° C.)(MH⁺) 9A

246-249 509.2293 9B

204-208 488.2895 9C

247-249 546.1978 9D

249-251 567.1407 9E

206-209 504.2848 9F

244-247 525.2242 9G

201-204 484.2630 9H

222-226 505.2039 9I

226-229 451.3060 9J

229-232 472.2474 9K

268-271 455.2577 9L

212-216 476.1975 9M

229-232 450.3126 9N

246-251 434.3168 9O

192-205 — 9P

185-196 — 9Q

202-210 — 9R

203-206 — 9S

190-205 — 9T

180-205 — 9U

258-262 —

Using a similar procedure described below, compounds wherein R is4-ethoxynaphthyl were also prepared:

Steps 1-3: See Example 9.

Step 4A: 4-Hydroxynaphthaldehyde (0.86 g) and K₂CO₃ (1.38 g, 2 equiv.)in CH₃CN (35 ml) were treated with CH₃CH₂₁ (0.80 ml, 2 equiv.), and theresulting mixture was stirred at RT for 20 h. The reaction mixture wasconcentrated in vacuo, the residue treated with EtOAc, and the mixturefiltered. The filtrate was partitioned with H₂O. The dried (MgSO₄) EtOAcwas concentrated in vacuo to give an orange-brown residue (0.89 g). Thisresidue was placed on preparative thin layer plates (10, 1000μ), andeluted with CH₂Cl₂ to give the title compound (0.82 g).

Step 4: Under argon, the products of step 3 (0.270 g; 0.95 mmol) andstep 4A (0.571 g; 2.9 mmol) in CH₂Cl₂ (25 ml) were stirred at RT for 30min. Na(OAc)₃BH (0.506 g; 3.4 mmol) was added. After 19 h, the reactionmixture was quenched with dilute NaOH. The aqueous layer was washed withCH₂Cl₂ (3×). The combined CH₂Cl₂ solution was washed with H₂O (3×) andthen brine. The dried (MgSO₄) CH₂Cl₂ solution was concentrated to −50ml. Amberlyst 15 (4.5 meq/g: 2.4 g; 11.025 mmeq) was added. After 19 h,additional Amberlyst 15 (2.3 g) was added. After 7 h, the resin waswashed with CH₂Cl₂ (5×), THF (5×), THF:H₂O (5×), H₂O (5×), CH₃OH (5×)and CH₂Cl₂ (5×). The resin was eluted with 2M NH₃ in CH₃OH (300 ml)(3×), followed by concentration in vacuo to give an amber oil (0.215 g).The crude material was placed on preparative thin layer plates (4,1000μ), and eluted with CH₂Cl₂:2M NH₃ in CH₃OH (9:1) to give an amberoil (0.125 g, 36%).Step 5: Using the appropriate carboxylic acid in the procedure ofExample 9, step 5, the following compounds were prepared:

LCMS found M+H=531; HPLC* Retention time 5.52 min.

LCMS found M+H=516; HPLC* Retention time 5.66 min.

*HPLC: VYDAC 218TP5405 column; gradient 5-95% B over 10 min hold 2 min;Soln A 0.1% TFA/H₂O, Soln B 0.1% TFA/CH₃CN at 245 nm.

Using a similar procedure wherein the starting piperazine does not havethe methyl substituent, the following compound was prepared:

EXAMPLE 10

Step 1: A solution of 4-N-BOC-2(S)-methyl piperazine (0.4 g; 2 mmol),p-iodobenzaldehyde (0.46 g; 2 mmol) and NaBH(OAc)₃ (0.65 g; 3 mmol) in 6ml of CH₂Cl₂ was heated at gentle reflux for 14 h. The contents werecooled, diluted with 30 ml of CH₂Cl₂ and washed with 1N NaOH solution,water and brine to isolate an yellow oil (0.8 g). FSGC (25%EtOAc-hexane) afforded the desired product (0.66 g; 79%) as a colorlessfilm. TLC R_(f)=0.6 in 25% EtOAc-hexane

The BOC protecting group was removed from the product (0.66 g; 1.58mmol) by treatment with TFA (1 ml) in CH₂Cl₂ (2 ml). Following standardwork up, the mono-alkylated piperazine (0.5 g; 100%) was obtained as acolorless gum.

Step 2: NaBH(OAc)₃ (0.63 g; 3 mmol) and two drops of AcOH were added toa solution of the product of step 1 (0.5 g; 1.58 mmol) andN-BOC-piperidinone (0.6 g; 3 mmol) in 5 ml of CH₂Cl₂ and the resultingsolution was stirred at ambient temperature for 16 h. After the usualwork up and FSGC, the desired product (0.6 g; 76%) was obtained as acolorless oil. TLC R_(f)=0.4 in 25% acetone-CH₂Cl₂.

The free piperidine (0.38 g; 79%) was prepared from the N-BOC protectedcompound (0.6 g; 1.2 mmol) by treatment with TFA (2 ml) in CH₂Cl₂ (5ml).

Compound 10A: The coupling of 6-chloro anthranilic acid (0.065 g; 0.38mmol) with the product of step 2 (0.127 g; 0.32 mmol) in the presence ofDEC (0.092 g; 0.48 mmol), HOBT (0.065 g; 0.48 mmol) and diisopropylethylamine (0.1 ml), followed by product isolation, were carried out asdescribed previously. This procedure furnished the compound 10A (0.13 g;73%) as a colorless film. TLC R_(f)=0.5/0.45 for a pair of rotomers in2% CH₃OH—CH₂Cl₂.

The HCl salt of the title compound was prepared in the usual manner. Mp:198-202° C.; HRMS (MH⁺)=553.1231.

Compound 10B: Coupling the product of step 2 with 6-methyl anthranilicacid gave compound 10B (HCl salt) in 73% yield. Mp: 197-200° C.; HRMS(MH⁺)=533.1774.

Compound 10C: 2,6-Dimethyl benzoic acid was coupled to the product ofstep 2 to obtain the amide 10C(HCl salt) in 50% yield. Mp: 202-205° C.;HRMS (MH⁺)=532.1826.

EXAMPLE 11

Step 1: (S)-Methylbenzylamine (27 ml, 0.2 mol) in CH₂Cl₂ (50 ml) wasdropped into ice-cold trifluoroacetic anhydride (40 ml) in CH₂Cl₂ (200ml) within 15 min. The mixture was stirred at RT for 1 h, then cooled inan ice water bath, iodine was added (27 g, 0.106 mol) and then[bis(trifluoro-acetoxy)iodo]-benzene (25 g, 0.058 mol). After beingstirred at RT overnight in the dark, more[bis(trifluoroacetoxy)iodo]benzene (24 g, 0.056 mol) was added and themixture was stirred at RT for one more day. The mixture was diluted withCH₂Cl₂ (500 ml) and ice-cold Na₂SO₃ (10% aqueous, 500 ml) and stirredfor 0.5 h. The organic layer was separated and washed with NaHCO₃,filtered through a short silica gel column and washed with CH₂Cl₂ (500ml). After CH₂Cl₂ was evaporated, Et₂O (125 ml) was added and themixture stirred for 10 min. Hexanes (600 ml) was added gradually to theEt₂O solution and the mixture was stirred for 0.5 h. The precipitate wascollected and washed with hexanes. The white solid was dried at RT andiodo compound (36.5 g, 53% yield, R_(f)=0.7, EtOAc/hexanes, 1:3) wasobtained.Step 2: The product of step 1 (11.2 g, 0.033 mol) was dissolved in CH₃OH(200 ml) and NaOH (15 g, 0.375 mol) in water (100 ml) was addeddropwise. The mixture was stirred at RT for 2.5 h. After the CH₃OH wasevaporated, the aqueous layer was extracted with Et₂O (3×100 ml) and thecombined organic portion was washed with brine, dried over Na₂SO₄,filtered and concentrated to give a free amine.

Methyl-R-lactate (4.08 g, 0.039 mol) was dissolved in CH₂Cl₂ (40 ml) andthe mixture was stirred and cooled in acetone-CO₂ to −78° C. under N₂atmosphere. Trifluoromethane sulfonic anhydride (10.2 g, 0.036 mmol) andthen 2,6-lutidine (6.27 g, 0.059 mol) were added and the mixture wasstirred for 5 min at −78° C. The mixture was warmed to RT and stirredfor 30 min. More CH₂Cl₂ was added to the mixture and the solution waswashed with 2N HCl. The freshly prepared amine from above was added tothe triflate solution followed by K₂CO₃ (18 g, 0.132 mol) in water (20ml). The mixture was stirred at RT overnight. Extractive work-up withCH₂Cl₂ followed by silica gel column chromatography gave a secondaryamine (8.27 g, 75% yield, R_(f)=0.65, hexanes/EtOAc, 3:1) as a yellowsyrup.

Step 3: The amine of step 2 (17.3 g, 0.052 mol) was dissolved indichloroethane (100 ml) and ClCH₂COCl (117.2 g, 82 ml, 1.04 mol). Themixture was stirred under reflux condition for 3 h. Both the solvent andClCH₂COCl were removed under vacuum. The remaining yellow syrup wasdissolved in DMSO (40 ml) at 0° C. and NaI (5.2 g, 0.035 mol) and NH₄OH(56 ml, 1.04 mol) were added. The reaction mixture was stirred 0° C. for30 min., warmed up to RT and stirred overnight. Water (100 ml) was addedto the mixture and the precipitate was filtered and washed with water.The white solid obtained was dried in air to give the diketopiperazine(14.3 g, 77% yield, R_(f)=0.56, hexanes/EtOAc, 3:1).

Step 4: The diketopiperazine of step 3 (14.3 g, 0.04 mol) was dissolvedin dimethoxy ethane (200 ml) and NaBH₄ (15.1 g, 0.4 mol) and BF₃.OEt₂(34 g, 29.5 ml, 0.24 mol) were added to the solution. The mixture wasstirred under reflux conditions for 3 h and then cooled to about 0° C.on a ice bath. CH₃OH (500 ml) and then concentrated HCl (300 ml) wereadded slowly to the mixture. The solution was stirred for 20 min. at RTand then under reflux conditions for 45 min. The mixture wasconcentrated and NaOH was added until the pH was more than 10.Extractive work up with EtOAc gave the desired piperazine as a yellowsyrup (12.9 g, 98% yield).

Step 5: The product of step 4 (1.9 g, 5.79 mmol), N-BOC-4-piperidone(5.73 g, 28.8 mmol), NaBH(OAc)₃ (6.1 g, 28.8 mmol) and 2M AcOH (5.76 ml,11.52 mmol) were combined in CH₂Cl₂ (150 ml) and the mixture was stirredovernight. After the solvent was removed, NaOH (3N) was added andextractive work up with EtOAc followed by silica gel chromatographyafforded pure piperazino-piperidine (2.21 g, 75% yield, R_(f)=0.18,hexanes/EtOAc, 1:1) as a syrup.

Step 6: The product of step 5 (1.9 g, 3.7 mmol) was dissolved in CH₂Cl₂(10 ml) and TFA (10 ml) was added. The mixture was stirred at RT for 2h. After the removal of the solvent and TFA under reduced pressure, NaOHsolution (3N) was added to the remaining syrup and extractive work upwith EtOAc gave the free piperazino-piperidine (1.3 g, 85% yield) as ayellow syrup. To a solution of the free piperazino-piperidine (200 mg,0.484 mmol) in CH₂Cl₂ (2 ml) were added 2,6-dimethylbenzoic acid (150mg, 0.99 mmol), DEC (191 mg, 0.99 mmol) and HOBT (135 mg, 0.99 mmol).The mixture was stirred at RT overnight and then the solvent was removedunder reduced pressure. NaOH solution (3N) was added to the remainingsyrup and extractive work up with EtOAc followed by columnchromatography afforded the title compound (210 mg, 80% yield,R_(f)=0.37, CH₂Cl₂/CH₃OH, 20:1). HRMS (as the HCl) calcd for C₂₇H₃₇N₃01(M+H⁺) 546.1981, found 546.1965. Mp: 190° C. (dec.).

Using a similar procedure, compounds of the formula

were prepared, wherein R⁹ and R¹⁰ are as defined in the table:

EXAMPLE 12

Ex R⁹ R¹⁰ Mp (° C.) HRMS 11A —CH₃ —NH₂ 198 (dec.) 547.1928 11B —Cl —NH₂203 (dec.) 567.1395 11C —OH —OH 200 (dec.) 550.1555 11D —OCH₃ —OCH₃ 200(dec.) 578.1860Step 1: To the solution of the product of Example 11, step 4 (1.4 g, 4.2mmol) and 1-tert-butoxycarbonyl-4-piperidone (0.93 g, 4.67 mmol) inCH₂Cl₂ was added Ti(OiPr)₄ (1.19 g, 4.2 mmol) and the mixture wasstirred at RT overnight. 1M Et₂AlCN (5.04 ml, 5.04 mmol) was added, themixture was stirred overnight at RT and the solvent was evaporated.Saturated NaHCO₃ was added to the residue and extractive work up withEtOAc gave the Strecker amine as a yellow syrup. The syrup was dissolvedin THF (40 ml) and 3M CH₃MgBr (7 ml, 21 mmol) was added to the solution.The mixture was stirred at RT overnight, then cooled to 0° C. andsaturated NH₄Cl and water was added. Extractive work up with EtOAcfollowed by silica gel chromatography gave the piperazino-piperidineproduct (1.78 g, 81% yield, R_(f)=0.52, hexanes/EtOAc, 2:1).Step 2: Treat the product of step 1 in the manner described in Example11, Step 6, to obtain the title compound. Mp. 190° C. (dec.); HRMS (asthe HCl salt): found 560.2145.

Using a similar procedure, compounds of the formula

were prepared, wherein R² is as defined in the table: Ex R² mp (° C.)HRMS 12A

145 (dec.) 581.1537 12B

150 (dec.) 561.2083 12C

208 (dec.) 561.2096 12D

206 (dec.) 562.1944 12E

190 (dec.) 577.2029 12F

245 (dec.) 601.1006 12G

218 (dec.) 577.2029 12H

195 (dec.) 617.0945 12I

116 (dec.) 562.2048

EXAMPLE 13

Step 1: To a solution of the N-BOC protected product of Example 11, step4 (250 mg, 0.581 mmol) in DMF (2.5 ml), CuCl (1 g, 10.1 mmol) was added.The suspension was stirred under N₂ at 110° C. for 24 h. After themixture was cooled to RT, NH₄OH was added and the solution graduallyturned bright blue. Extractive work up with EtOAc gave a mixture of thechloro-substituted piperazine and its BOC derivative. After treating themixture with TFA (5 ml) in CH₂Cl₂ (2 ml) for 2 h, the solvent wasevaporated and NaOH (3N) was added. Extractive work up with EtOAcafforded the pure piperazine (110 mg, 79%) as a yellow syrup.Step 2: The product of step 1 was treated in a manner similar to Example11, steps 5 and 6, to obtain the title compound. Mp. 180° C. (dec.);HRMS (as the HCl salt): found 454.2617.

Using a similar procedure, compounds of the formula

were prepared, wherein R⁹ and R¹⁰ are as defined in the table: Ex R⁹ R¹⁰Mp (° C.) HRMS 13A —CH₃ —NH₂ 200 (dec.) 455.2577 13B —Cl —NH₂ 200 (dec.)475.2023 13C —Cl —Cl 187 (dec.) 494.1536

Using the product of step 1 in the procedure of Example 12, compounds ofthe formula

were prepared, wherein R² is as defined in the table: Ex R² Mp (° C.)HRMS 13D

197 (dec.) 468.2779 13E

205 (dec.) 489.2184 13F

210 (dec.) 469.2734 13G

195 (dec.) 470.2689 13H

260 (dec.) 509.1634 13I

200 (dec.) 485.2688

EXAMPLE 14

Step 1: To a solution of the N-BOC protected product of Example 11, step4 (5 g, 0.012 mol) in DMF (20 ml), CuCN (20.8 g, 0.23 mol) was added.The suspension was stirred under N₂ at 110° C. for 22 h. After themixture was cooled to RT, NH₄OH was added and the solution graduallyturned bright blue. Extractive work up with EtOAc followed by silica gelcolumn chromatography gave the cyano derivative (2.29 g, 60% yield,R_(f)=0.5, hexanes/EtOAc, 4:1), the carboxamide derivative (0.95 g,23.6% yield, R_(f)=0.2, CH₂Cl₂/CH₃OH, 10:1) and the unsubstitutedderivative (85 mg, 2.4% yield, R_(f)=0.75, hexanes/EtOAc, 2:1).Step 2: The BOC group on the cyano compound of step 1 was first removedunder acidic conditions and the resultant amine was converted to thetitle compound following the procedure of Example 11, steps 5 and 6.HRMS (as the HCl salt): found 445.4970.

EXAMPLE 15

Step 1: To a solution of the N-BOC protected product of Example 11, step4 (1.4 g, 3.26 mmol) and CuCl (1.61 g, 16.3 mmol) in CH₃OH at 0° C. wasadded NaBH₄ (3.69 g, 97.6 mmol) slowly. A black precipitate was formed.The mixture was warmed to RT and stirred overnight. The precipitate wasremoved by celite filtration and CH₃OH was removed under vacuum.Extractive work up with EtOAc afforded the desired compound (1 g, 100%yield, R_(f)=0.55, hexanes/EtOAc, 5:1) as a syrup.Step 2: The BOC group on the product of step 1 was removed under acidicconditions and the resultant amine was converted to the title compoundfollowing the procedure of Example 11, steps 5 and 6.

Mp. 195° C.; HRMS (as the HCl salt): found 420.3016.

Using a similar procedure, the following compound is prepared:

HRMS (as the HCl salt): found 441.2426

EXAMPLE 16

Step 1: To a solution of the N-BOC protected product of Example 11, step4 (2.5 g, 5.8 mmol) in benzene were added phenyl boric acid (1.68 g,13.8 mmol), 2M Na₂CO₃ (14 ml) and tetrakis(tri-phenyl phosphine)palladium (0.67 g, 0.58 mmol). The mixture was stirred under refluxovernight. Extractive work up with EtOAc followed by silica gel columnchromatography gave the phenyl derivative (1.37 g, 62% yield, R_(f)=0.5,hexane/EtOAc, 5:1) as a syrup.Step 2: The BOC group on the product of step 1 was removed under acidicconditions and the resultant amine was converted to the title compoundfollowing the procedure of Example 11, steps 5 and 6.

Mp. 190° C.; HRMS (as the HCl salt): found 496.3319.

Using a similar procedure, compounds of the formula

were prepared, wherein R² is as defined in the table: Sch Ex R² Mp (°C.) HRMS 223254 16A

190 (dec.) 517.2754 223255 16B

65-70* 497.3287 2?5666 16C

190 (dec.) 498.3225*free base

EXAMPLE 17

Step 1: The N-BOC protected product of Example 11, step 4 (800 mg, 1.88mmol) was dissolved in dry THF and the temperature was brought to −78°C. under N₂. Butyl lithium (2.5 M solution, 0.832 ml, 2 mmol) was addedand the mixture was stirred at −78° C. for 10 min. The solution then wasdropped into p-chlorobenzyl aldehyde (234 mg, 2.07 mmol) in THF at −78°C. The mixture was stirred for 30 min. at −78° C., then gradually warmedup to RT. Saturated NH₄Cl was added to the mixture and extractive workup with EtOAc followed by silica gel column chromatography gave thedesired alcohol (30 mg, 3.6% yield, R_(f)=0.5, hexanes/EtOAc, 2:1) as ayellow syrup.Step 2: A solution of alcohol of step 1 (40 mg, 0.090 mmol),triethylsilane (52 mg, 0.45 mmol) and TFA (5 ml) in CH₂Cl₂ (5 ml) wasstirred under reflux conditions for 2 h. After CH₂Cl₂, triethylsilaneand TFA were removed under reduced pressure, NaOH solution (3N) wasadded to the remaining syrup. Extractive work up with EtOAc afforded thechlorobenzyl derivative (20 mg, 68% yield) as a yellow syrup.Step 3: The product of step 2 was converted to the title compoundfollowing the procedure of Example 11, steps 5 and 6. Mp. 170° C.(dec.); HRMS (as the HCl salt): found 544.3101.

EXAMPLE 18

Step 1: To a solution of the N-BOC protected 4-piperidinyl derivative ofthe cyano compound of Example 14, step 1 (510 mg, 1.24 mmol) in Et₂O (4ml) was added 3M CH₃MgBr (4 ml) in a dropwise manner. The mixture wasstirred under reflux overnight. After the solution was cooled onice-bath, 12N HCl (4 ml) was added and the mixture was stirred on asteam bath for 2 h. The solution was cooled to RT and solid NaOH pelletswere added until the pH was more than 10. Extractive work up withEtOAc/CH₃OH (3:1) afforded the desired methyl ketone (249 mg, 61% yield)as a syrup.Step 2: The product of step 1 was treated according to the standard DECpeptide coupling procedures of Example 11, step 6, to obtain the titlecompound. Mp. 210° C.; HRMS (as the HCl salt): found 483.2522.

Using a similar procedure, the following compound is prepared:

Mp. 210° C. (dec.); HRMS (as the HCl salt): found 463.3088

EXAMPLE 19

Step 1: To a solution of the product of Example 22 (140 mg, 0.29 mmol)in CH₃OH (10 ml) and EtOH (1 ml) were added NH₂OCH₃—HCl (738 mg, 8.84mmol) and NaOAc (725 mg, 8.84 mmol). The suspension was stirred at 40°C. overnight, the solvents were evaporated and water was added to theresidue. Extractive work up with EtOAc followed by silica gelchromatography generated the title compound (99 mg, 68% yield,R_(f)=0.38, CH₂Cl₂/CH₃OH, 20:1). HRMS (as the tartrate) calc'd. forC₃₁H₄₅N₄O₂ (M+H⁺) 505.3543; found 505.3542.

Using a similar procedure, compounds of the formula

were prepared, wherein R⁸, R⁶ and R² are as defined in the table: Ex R⁸R⁶ R² mp (° C.) HRMS 19A

H

194 (dec.) 512.2785 19B

H

150 (dec.) 492.3344 19C

H

— 506.3494 19D

—CH₃

180 (dec.) 508.3296 19E

—CH₃

195 (dec.) 493.3291

EXAMPLE 20

Dissolve the free piperazino-piperidine of Example 11, step 6 (1.7 g,3.3 mmol) in CHCl₃ (30 ml; =Stock solution A). Add 250 ul of stocksolution A (0.027 mmol) to a slurry of 0.15 g (0.14 mmol) of resin boundcardodiimide (prepared by reacting Argopore-CI resin with1-(3-dimethyl-aminopropyl)₃-ethyl carbodiimide in DMF at 100° C. in DMF(1.5 ml) in a polyethylene SPE cartridge. To this mixture add 75 ul of a1 M solution of 5-methyl-3-phenylisoxazole-4-carboxylic acid in DMF(0.075 mmol), and HOBT (24 ul of a 1M solution in DMF). Shake thismixture for 14 h, filter and add 0.1 g of Amberlyst-15 resin (0.47 mmol)to the filtrate. Shake for 1 to 2 h, filter and wash the resin twicewith each of the following solvents THF, CH₂Cl₂ and CH₃OH, then washwith THF and CH₂Cl₂. Treat the resin with 2M NH₃ in CH₃OH (1 time for 30min, and 1 time for 5 min). Combine and concentrate the filtrates underreduced pressure to afford the title compound. LCMS found MH⁺=599.1(calculated MW 598); TLC R_(f)=0.74 (CH₂Cl₂/CH₃OH/NH₄OH (95/5/0.5)).

Using the procedure above with the appropriate carboxylic acids gave thefollowing compounds

wherein R² is as defined in the table: LCMS TLC Ex. R² results R_(f)values 20A

MH⁺ = 600.1 R_(t) = 6.56 min. 0.92 20B

MH⁺ = 601.1 R_(t) = 5.69 min. 0.63 20C

MH⁺ = 560.1 R_(t) = 5.77 min. 0.60 20D

MH⁺ = 588.1 R_(t) = 6.61 min. 0.66 20E

MH⁺ = 604.1 R_(t) = 5.60 min. 0.87 20F

MH⁺ = 658.2 R_(t) = 5.69 min. 0.86 20G

MH⁺ = 606.1 R_(t) = 6.17 min. 0.43 20H

MH⁺ = 568.1 R_(t) = 5.67 min. 0.57 20I

MH⁺ = 586.1 R_(t) = 6.02 min. 0.63 20J

MH⁺ = 558.1 R_(t) = 5.35 min. 0.33 20K

MH⁺ = 546.1 R_(t) = 5.37 min. 0.52

EXAMPLE 21

Step 1: The BOC group on the cyano compound of Example 14, step 1, wasfirst removed under acidic conditions and the resulting amine (1.59 g,6.96 mmol), 1-tert-butoxycarbonyl-4-piperidone (1.66 g, 8.35 mmol) andTi(OiPr)₄ (2.18 g, 7.66 mmol) in CH₂Cl₂ were stirred at RT overnight. 1MEt₂AlCN (8.35 ml, 8.35 mmol) was added, the mixture was stirredovernight at RT and the solvent was evaporated. Saturated NaHCO₃ wasadded to the residue and extractive work up with EtOAc followed bycolumn chromatography gave the Strecker amine as a yellow syrup (1.76 g,58% yield, R_(f)=0.70, Hexanes/EtOAc, 2:1).Step 2: The amine of Step 1 (200 mg, 0.46 mmol) was dissolved inanhydrous THF (2 ml) and 3M CH₃MgBr (0.76 ml, 2.29 mmol) was addeddropwise. The mixture was stirred at RT overnight and then cooled to 0°C. Saturated NH₄Cl (10 ml) was added and a precipitate appeared. Water(40 ml) was addded and the precipitate disappeared. Extractive work upwith EtOAc followed by column chromatography gave the desiredipso-methyl derivative (169 mg, 86% yield, R_(f)=0.53, Hexanes/EtOAc,2:1).Step 3: The product of step 2 was treated in the manner described inExample 11, Step 6, to obtain the title compound. Dec. 198° C.; HRMS (asthe HCl salt): found 460.3079.

Using a similar procedure, compounds of the formula

were prepared, wherein R² is as defined in the table: Ex R² Mp (° C.)HRMS 21A

205 (dec.) 480.2532 21B

 65-75* 476.3033 21C

250 (dec.) 500.1992 21D

195 (dec.) 461.3019*Mp for the free amine

EXAMPLE 22

Step 1: The Strecker amine from Example 21, step 1 (380 mg, 0.87 mmol)was treated with CH₃MgBr (2.9 ml, 8.7 mmol) in Et₂O (5 ml) under refluxconditions overnight. The mixture was cooled on ice and water (5 ml) wasadded dropwise. 12N HCl (6 ml) was added and the mixture was stirred ona steam bath for 2 h. After the mixture was cooled on ice, NaOH wasadded until the pH of the solution was above 10. Extractive work up withEtOAc afforded a free amine as a syrup (307 mg, 100% yield).Step 2: The product of step 1 was converted to the title compoundfollowing the peptide coupling procedure described in Example 11, step6. Mp. 80-85° C.; HRMS found 476.3271.

Using a similar procedure, compounds of the formula

were prepared, wherein R² is as defined in the table: Ex. R² Mp (° C.)HRMS 22A

195 (dec.) 493.3172 22B

200 (dec.) 478.3178

EXAMPLE 23

Steps 1-3:

Step 1: Ethyl diacetoacetate (93.4 g), Cs₂CO₃ (185 g) and CH₃CN (550 ml)were mixed together, using an overhead mechanical stirrer. CH₃CN (50 ml)was added and the resulting mixture was cooled to 0° C. Methyltrifluoromethane sulfonate (88.6 g) was added dropwise and afteraddition, the cooling bath was removed. The mixture was stirred for 1 hat RT, filtered, and the salts were washed with Et₂O (2×50 ml). Theorganic extracts were combined and Et₂O (300 ml) was added. Theresulting mixture was filtered, the filter cake was washed with Et₂O(2×100 ml), the Et₂O extracts were combined and evaporated to halfvolume. The solution was cooled in an ice bath and washed once withcooled (0° C.) 2 N NaOH (pH=11). The Et₂O layer was dried over MgSO₄,filtered and evaporated to give the desired product as a yellow liquid(64.7 g) in 65% yield, which was used directly in the next step.Step 2: The product of step 1 (64.2 g), sodium ethoxide in ethanol(commercial solution; 21 wt %; 113 g) ethanol (587 ml) and formamidineacetate (36.2 g) were mixed together at RT. After refluxing for 4 h, themixture was cooled to RT, the resulting precipitate was filtered off andthe ethanol was removed under vacuum. The resulting liquid waspartitioned between water and CH₂Cl₂ and the aqueous layer was extractedwith CH₂Cl₂ (3×150 ml). The CH₂Cl₂ extracts were dried over MgSO₄,filtered and evaporated to give a dark crude liquid (50.7 g) which waspurified by silica gel chromatography (980 g; 4:1 hexanes:EtOAc aseluant). After evaporation of the appropriate fractions, the desiredproduct (28.5 g) was isolated in 46% yield and used directly in the nextstep.Step 3: The product of step 2 (28.1 g), NaOH (6.72 g), water (65 ml) andEtOH (130 ml) were mixed together at RT and heated at reflux for 1 h.The resulting solution was cooled to RT and the volatile materials wereremoved in vacuo until a thick paste resulted. Water (20 ml) was added,the mixture was cooled to 0° C. and conc. HCl (14.3 ml) was addeddropwise with stirring. The resulting white precipitate was collected byfiltration, washed with ice water (2×10 ml) and air dried with suctionfor 30 min. The resulting white solid was treated with toluene (2×20ml), the solvent was removed in vacuo at 50° C. and then dried undervacuum (1 mm Hg) for 18 h. The desired product (14.9 g) was isolated asa white solid in 63% yield, mp: 176-178° C. Elemental analysis ofC₇H₈N₂O₂: calc'd C 55.26%, H 5.30%, N 18.41%; found: C 55.13%, H 5.44%,N 18.18%.

A second crop of product was isolated by evaporation of the aqueousfiltrate (from above) to dryness and addition of water (20 ml). Theresulting mixture was stirred at RT for 5 min, cooled in an ice bath andthe precipitate formed was collected by filtration. The resulting solidwas washed with ice water (2×5 ml) and dried as described above to givethe product (4.68 g) as a cream colored solid to give a combined yieldof 83%.

Step 4: The product of Example 4, step 6 (trihydrochloride form; 5.4 g),DMF (11.3 ml), HOBt (3.07 g), diisopropyl ethyl amine (12.3 ml) and theproduct of step 3 (3.45 g) were mixed together and DEC (4.35 g) wasadded in portions over 15 min. The resulting mixture was heated at 45°C. for 18 h, cooled to RT, diluted with EtOAc (80 ml) and washed with 2N NaOH (25 ml). The aqueous layer was extracted with EtOAc (3×25 ml),the organic extracts were combined, washed with brine, dried overNa₂SO₄, filtered and evaporated. The resulting crude oil was purified bysilica gel chromatography (170 g; 76:19:5 hexanes:EtOAc:Et₃N as eluant).After evaporation of the appropriate fractions, the free base form ofthe title compound (5.21 g) was isolated as a light colored foam in 91%yield.

Step 5: To a cooled (0° C.) solution of the free base of step 4 (2.00 g)and EtOAc (20 ml) was added HCl (3.0 ml of a 4.0 M solution in1,4-dioxane). The resulting mixture was warmed to RT, diluted with Et₂O(20 ml), filtered, washed with Et₂O (2×20 ml), air dried with suctionfor 10 min and then under vacuum (1 mm Hg) at 90° C. for 5 h to give thetitle compound (2.30 g) as a white solid in 97% yield. mp: 159-162° C.Elemental analysis of C₂₇H₃₆N₅OF₃.2HCl.0.5H₂O: calc'd: C 55.38%, H6.71%, N 11.96%, Cl 12.11%; found: C 55.19%, H 6.69%, N 11.75%, Cl11.45%.

Additional pyrimidine derivative-compounds were made using similarprocedures:

Steps 1-2:

Step 1: The product of Example 23, step 1 was treated in the same manneras in Example 23, step 2, substituting acetamidine hydrochloride (2.03g) for formamidine acetate. The amounts of the reagents were: product ofExample 23, step 1 (4.0 g), ethanol (20 ml) and sodium ethoxide inethanol (commercial solution; 21 wt %; 8.03 g). After extraction andpurification as described above, the product was isolated (1.7 g) as acolorless liquid in 41% yield, which was used directly in the next step.Step 2: The product of step 1 (1.7 g) was treated in the same manner asExample 23, step 3, using ethanol (5 ml), water (5 ml) and NaOH (1.0 g).After extraction and purification as described above, the product wasisolated (0.12 g) as a white solid in 8% yield, which was used directlyin the next step.Step 3: The product of Example 4, step 6 (0.05 g), and the product ofstep 2 (immediately above) (0.028 g) were subjected to the same reactionconditions as in Example 23, step 4, using HOBt (20 mg), DEC (45 mg),diisopropyl ethylamine (40 mg) and DMF (1.5 ml). After extraction andpurification as described above, the product was converted to its HClsalt using the procedure outlined for Example 23, step 5 to give thetitle compound (77 mg) as a white solid in 97% yield over the two steps.mp: 185-190° C.

Steps 1-2:

Step 1: The product of Example 23, step 1 was treated in the same as inExample 23, step 2, substituting benzamidine hydrochloride (3.35 g) forformamidine acetate. The amounts of the reagents were: product ofExample 23, step 1 (4.0 g), ethanol (20 ml) and sodium ethoxide inethanol (commercial solution; 21 wt %; 8.03 g). After extraction andpurification as described above, the product was isolated (4.5 g) as aliquid in 82% yield which was used directly in the next step.Step 2: The product of step 1 (4.5 g) was treated in the same manner asExample 23, step 3, using ethanol (10 ml), water (10 ml) and NaOH (2.0g). After extraction and purification as described above, the productwas isolated (3.0 g) as a white solid in 77% yield which was useddirectly in the next step.Step 3: The product of Example 4, step 6 (75 mg), and the product ofstep 2 (immediately above) (39 mg) were subjected to the same reactionconditions as in Example 23, step 4, using HOBt (35 mg), DEC (53 mg),diisopropyl ethylamine (100 mg) and DMF (2 ml). After extraction andpurification as described above, the product was converted to its HClsalt using the procedure outlined for Example 23, step 5 to give thetitle compound (98 mg) as a white solid in 96% yield over the two steps.mp: 250-253° C.

Steps 1-2:

Step 1: The product of Example 23, step 2 (528 mg) was dissolved inCH₂Cl₂ (5.0 ml) and meta-chloroperbenzoic acid (mCPBA) (600 mg) wasadded in three portions at RT. The resulting mixture was stirred at RTfor 24 h and CH₂Cl₂ (2 ml) and mCPBA (200 mg) were added. After 3 h, themixture was poured onto a silica gel column (40 g) and eluted with 1:1hexanes:EtOAc and then 10:1 CH₂Cl₂:CH₃OH. After evaporation of theappropriate fractions, the product was isolated (512 mg) as a waxy whitesolid in 89% yield, which was used directly in the next step.Step 2: The product of step 1 was dissolved in CH₃OH (1.8 ml) and asolution of 1.0 M Na₂CO₃ (1.5 ml) was added. After stirring at RT for 36h, the resulting mixture was evaporated to dryness, toluene (2 ml) wasadded and the mixture was evaporated to dryness. The resulting crudesolid (153 mg) was used directly in the next step without purification.Step 3: The product of Example 4, step 6 (94 mg), and the product ofstep 2 (immediately above) (76 mg) were subjected to the same reactionconditions as in Example 23, step 4, using HOBt (92 mg), DEC (130 mg),diisopropyl ethylamine (0.14 ml) and DMF (0.25 ml). After extraction andpurification by preparative thin layer chromatography (1000 μM silicaplate; 95:5 EtOAc:Et₃N eluant), the free base form of the title compoundwas isolated (52 mg) as a foam in 40% yield. HRMS: calc'd: M′H⁺:C₂₇H₃₇N₅O₂F₃: 520.2899; measured: 520.2908.Step 4: The product of step 3 (52 mg) was subjected to the reactionconditions in Example 23, step 5, using EtOAc (1.0 ml) and HCl (4.0 Msolution in 1,4-dioxane; 75 μl) to give, after work up, the titlecompound (44.5 mg) as a white solid in 76% yield. mp: decompostion above161° C.

Using similar procedures, the compounds of the formula

were also prepared, wherein R^(8a) and R¹¹ are as defined in the table:Ex. R^(8a) R¹¹ m.p. (° C.) 23D —CF₃ —OH 175-185 23E —CF₃ —OCH₃ 169-17323F —CF₃ —NH₂ 200-210 23G —CF₃ —NHCONHEt 184-190 23H —CF₃ —CF₃ 83-86 23I—CF₃

154-159 23J —CF₃ —SCH₃ >176 (dec) 23K —OCF₃ —CH₃ 205-210 23L —OCF₃ Ph239-242 23M —OCF₃ —OCH₃ 200-210 23N —OCF₃ —OH 185-191

EXAMPLE 24 Arylcyclopropylamides

Step 1: To the stannane (0.39 g, 0.95 mmol) in DMF (10 ml) was added the2-chloro-4-fluoroiodobenzene (0.73 g, 2.86 mmol), CuI (0.19 g, 1.05mmol) and tetrakis(triphenylphosphine)palladium (0) (0.11 g, 0.095mmol). The reaction was stirred at RT under N₂ for 21 h. The reactionmixture was added to Et₂O and the heterogeneous solution filteredthrough a bed of celite, washing with EtOAc. The filtrate was washedwith water and brine and dried (MgSO₄). Filtration and evaporation ofthe solvent in vacuo afforded a residue that was preadsorbed on silicagel. Purification by silica gel chromatography (4% EtOAc/hexane) yieldedthe arylacrylate (0.19 g, 78%), which was used directly in the nextstep.Step 2: To trimethylsulfoxonium iodide (0.18 g, 0.81 mmol) in DMSO (1.6ml) was added potassium tert-butoxide (0.09 g, 0.81 mmol). The reactionmixture was stirred at RT for 1 h, at which time the arylacrylate (0.19g, 0.74 mmol) in DMSO (1.6 ml) was added. The reaction mixture wasstirred at RT for 5 h and water was added. The mixture was extractedwith EtOAc. The combined organic layers were washed with water and brineand dried (MgSO₄). Filtration and evaporation of the solvent in vacuoafforded the arylcyclopropyl ester that was used directly by taking upinto CH₂Cl₂ (3 ml) and adding TFA (0.5 ml). The reaction mixture wasstirred at RT for 15 h and then concentrated in vacuo to afford thearylcyclopropylcarboxylic acid (0.14 g, 91%-2 steps). Without furtherpurification, the carboxylic acid was coupled to the product of example8, step 3, using the procedure of Example 8, step 4 to obtain 24A as theHCl salt. HRMS (M+H): found 566.2561.

To the 2-fluorophenylacetonitrile (0.80 g, 5.92 mmol),benzyltriethyl-ammonium chloride (0.03 g, 0.12 mmol), and1-bromo-2-chloroethane (1.70 g, 11.9 mmol) was added 50% aqueous NaOH(3.5 ml). The reaction was stirred at 45° C. for 21 h and ethyleneglycol was added (3 ml). The reaction was then warmed to 100° C. andstirred for 7 h. Upon cooling to RT, the reaction was diluted with waterand washed with EtOAc. The aqueous layer was acidified to pH 2-3 withaqueous 6N HCl. The acidified solution was extracted with Et₂O. Thecombined Et₂O extracts were washed with water and brine and dried(MgSO₄). Filtration and evaporation of the solvent in vacuo afforded apale yellow solid (1.06 g, 99%). The arylcyclopropyl acid was coupled tothe product of example 8, step 3, using the procedure of Example 8, step4 to obtain 24B as the HCl salt. HRMS (M+H): found 532.2949.

Using similar procedures, the compounds of the formula

were prepared, wherein

is as defined in the table: Ex.

HRMS (M + H) m.p. (° C.) 24C

— 240-245 24D

— >225 24E

— 172-176 24F

— 225-230 24G

— >225 24H

544.3151 — 24I

592.2150 — 24J

532.2956 — 24K

539.3003 — 24L

558.2949 — 24M

572.3107 — 24N

582.2910 — 24O

582.2910 — 24P

520.2609 — 24Q

515.2991

EXAMPLE 25

Step 1:

Cyclopropyl carboxaldehyde (3.4 ml), S-methyl N-BOC piperazine (8.28 g),CH₂Cl₂ (82 ml) and Ti(OiPr)₄ (15.80 ml) were mixed together and stirredat RT for 23 h, then the resulting solution was cooled to 0° C. andEt₂AlCN (1.0 M in toluene; 62.1 ml) was added. The solution was stirredfor 5 h at RT. A mixture of KF (20 g) and Celite (10 g) was added,followed by cautious addition of EtOAc (120 ml) and water (120 ml). Theresulting slurry was stirred for 15 min, filtered, washed with EtOAc(3×35 ml) and the EtOAc layer was removed, washed with brine, dried overNa₂SO₄, filtered and evaporated to give the desired intermediate (12.0g) which was used directly in the next step.Step 2:

To a 0° C. solution of 4-iodobenzotrifluoride (40 g) and THF (52 ml) wasadded isopropyl magnesium chloride (2.0 M in Et₂O; 74 ml). The resultingsolution was stirred at RT for 1 h and then added to a 0° C. solution ofthe product of step 1 (10.0 g) and THF (26 ml) over 10 min. The reactionsolution was warmed to RT, stirred overnight and EtOAc (50 ml) wasadded. After stirring for 10 min, 2 N NaOH (50 ml) was added and theresulting mixture was stirred for 30 min, filtered and the salts werewashed with EtOAc (3×20 ml). The combined EtOAc extracts were washedwith brine, dried over Na₂SO₄, filtered and evaporated to give the crudeproduct (28 g) as a gold oil which was chromatographed on silica gel (1kg), eluting with hexanes:EtOAc (8:1). Two diastereomeric products werecollected as a single fraction (15.9 g) and further purified by columnchromatography as described above to give intermediate A (R_(f)=0.47 in4:1 hexanes:EtOAc; 5.34 g), which was contaminated with an unidentifiedimpurity. (The second diastereomer B (R_(f)=0.29 in 4:1 hexanes:EtOAc)was also collected.)Step 3:

To a solution of A from Step 2 (3.96 g) and CH₂Cl₂ (120 ml) was addedDOWEX 50X2-100 ion exchange resin (15 g) and the resulting mixture wasshaken for 2.5 h at RT. The resin was filtered off and washed withCH₂Cl₂ (2×40 ml). The resin was treated with 7 N NH₃ in CH₃OH (30 ml),the resin was filtered off and this procedure was repeated two times.The CH₃OH extracts were combined and evaporated. The resulting oil wastreated with toluene:CH₂Cl₂ (1:1; 15 ml) and evaporated to give thepiperazine intermediate (0.80 g) as a clear oil. HRMS: calc'd: M·H+:C₁₆H₂₁N₂F₃:299.1735; measured: 299.1748.Step 4:

The product of Step 3 (0.57 g) was treated in the same fashion asExample 8, Step 1, using N-BOC 4-piperidone (0.42 g), CH₂Cl₂ (3.84 ml),Ti(OiPr)₄ (3.39 ml), Et₂AlCN (2.88 ml) and CH₃MgBr (3.0 M in Et₂O; 3.2ml) to give the desired product (0.78 g) as a clear oil in 82% yield.

Step 5: The product of Step 4 (0.12 g) was treated with AcOH:CH₂Cl₂(3:1, v:v; 1.4 ml) followed by BF₃.Et₂O (0.14 ml). After stirring for 1h, the resulting solution was diluted with CH₂Cl₂ (10 ml), cooled to 0°C. and the pH was adjusted to 10 with solid NaOH. Water (2 ml) was addedand the CH₂Cl₂ layer was removed. After further extraction (2×10 ml)with CH₂Cl₂, the organic layer was washed with water, brine, dried overNa₂SO₄, filtered and evaporated to give the free piperidine (80 mg) in81% yield.

Step 6: The product of Step 5 (57 mg) was treated in the same fashion asin Example 8, Step 4, using DMF (0.30 ml), HOBt (41 mg), DEC (57 mg),diisopropyl ethyl amine (0.08 ml) and 4,6-dimethyl 5-pyrimidinecarboxylic acid (43 mg); the reaction was stirred at 45° C. for 5 h.Purification of the crude oil was carried out by preparative platechromatography (silica adsorbent; 2000 μM; 76:19:5 EtOAc:hexanes:Et₃N aseluant) to give, after elution of the desired band (1:1 CH₂Cl₂:MeOH) andconcentration of solvent, the title compound (70 mg) as a clear oil in93% yield. The HCl salt was prepared as described for Example 8, Step 4(78 mg) in 100% yield. mp: 147-149° C.

Using a similar procedure, the following compound was prepared:

EXAMPLE 26

Step 1:

The desired compound was prepared in a manner similar to Example 25,Step 1, using p-trifluoromethyl benzaldehyde (20 g) instead ofcyclopropyl carboxaldehyde, to give, after work up, a mixture ofdiastereomers (22.7 g) in 59% yield.Step 2:

To a −70° C. solution of the product of step 1 (1.9 g) and THF (15 ml)was added NaHMDS (1.0 M in THF; 7.5 ml) followed by benzyl bromide (2ml). The cooling bath was removed and the resulting solution was stirredfor 45 min. Concentrated NH₄OH (10 ml) was added and the reaction wasstirred for 30 min. The resulting mixture was partitioned between waterand CH₂Cl₂, the CH₂Cl₂ extracts were removed and evaporated and thecrude oil was purified by column chromatography (silica gel; 2:1hexanes:CH₂Cl₂; 10:1 to 7:1 hexanes:EtOAc as eluant) to give, afterevaporation of the appropriate fractions, a mixture of intermediates(1.92 g) as a yellow foam.Step 3:

The mixture of Step 2 (1.91 g), CH₃CN (35 ml), sodium triacetoxyborohydride (4.0 g) and magnesium bromide etherate (2.25 g) were mixedand stirred at RT for 70 h. Water (25 ml) was added and then, gradually,a solution of Na₂CO₃ (10 g) in water (50 ml). After extraction withEtOAc (2×50 ml), drying and evaporation of the organic layer, theresulting oil was purified by preparative plate chromatography (5×2000mM silica plates; 6:1 hexanes:EtOAc as eluant). The less polar band wasremoved, treated with 1:1 methanol:CH₂Cl₂, filtered and evaporated togive intermediate A (0.84 g) as a white foam. HRMS: calc'd: M·H+:C₂₅H₂₉O₂N₂F₃:449.2407; measured: 4492416.

Step 4: The product of Step 3 (0.81 g) was treated in the same fashionas in Example 8, Step 3, using TFA (5 ml) and CH₂Cl₂ (10 ml), to give,after work up, the free piperazine (0.60 g) as a clear gum. HRMS:calc'd: M·H⁺: C₂₀H₂₃N₂F₃: 349.1892; measured: 349.1894.

Step 5: The product of Step 4 (0.39 g) was treated in the same fashionas in Example 8, Step 1, using N-BOC 4-piperidone (0.25 g), CH₂Cl₂ (8ml), Ti(OiPr)₄ (0.40 mg), Et₂AlCN (2 ml) and CH₃MgBr (3.0 M in Et₂O; 1.5ml) to give the desired BOC-protected piperidinyl intermediate (0.44 g)as a clear oil in 72% yield. HRMS: calc'd: M·H+: C₃₁H₄₂O₂N₃F₃:546.3307;measured: 546.3315.

Step 6: The product of step 5 (0.43 g) was treated in the same fashionas in Example 8, Step 3, using TFA (3 ml), CH₂Cl₂ (2 ml) and water (0.2ml) to give, after work up, the free piperidinyl intermediate (0.37 g)as a clear oil.

Step 7: The product of step 6 (50 mg) was treated in the same fashion asin Example 8, Step 4, using CH₂Cl₂ (3 ml), HOBt (28 mg), DEC (40 mg),diisopropyl ethyl amine (42 mg) and 4,6-dimethyl 5-pyrimidine carboxylicacid (24 mg); the reaction was stirred at RT for 2 days. Using theprocedure described in Example 8, Step 4, the HCl salt of the titlecompound was prepared (59 mg) in 91% yield (from the product of Step 5).M.p: 187-196° C. HRMS: calc'd: M·H⁺: C₃₃H₄₀ON₅F₃:580.3263; measured:580.3263.

Using a similar procedure, compounds of the formula

were prepared, wherein R^(8a), R³ and R² are as defined in the table:Ex. R^(8a) R³ R² Mp (° C.) 26B —CF3

86-92 26C —CF3

83-90 26D —CF3

195-205 26E —CF3

118-125 26F —OCF3

175-185 26G —OCF3

180-190 26H —OCF3

220-230 26I —OCF3

195-210 26J —OCF3

190-200 26K —OCF3

180-205 26L —OCF3

230-240 26M —OCF3

60-65 26N —OCF3

65-68 26O —OCF3

60-62 26P —CF3

256-258 26Q —CF3

254-256 (dec) 26R —CF3

249-250 (dec)

EXAMPLE 27

Step 1:

4′-Trifluoromethyl)propiophenone (2.02 g, 0.01 mol) and(S)-2-methyl-CBS-oxazaborolidine (1M in THF) (2.0 ml, 0.002 mol) in THF(10 ml) was cooled in an ice-bath and borane-methyl sulfide complex (2Min THF) (3 ml, 0.006 mol) was added dropwise to the mixture. The mixturewas stirred for 30 min at ₀° C. and CH₃OH was added slowly until nobubbles appeared. The solvents were removed under reduced pressure andHCl solution (1N) was added to the mixture. EtOAc extractive work upfollowed by silica gel chromatography afforded the alcohol (1.47 g) in72% yield.

Step 2: A solution of the product of Step 1 (4.32 g, 0.021 mol) and Et₃N(5.9 ml, 0.042 mol) in CH₂Cl₂ (20 ml) was cooled to 0° C. in ice bathand CH₃SO₂Cl (2.13 ml, 0.028 mol) was added dropwise. The mixture wasstirred at 0° C. for 1 h and the ice bath was removed. Water was addedto the mixture and CH₂Cl₂ extractive work up afforded the mesylate (5.99g) in quantitative yield.

Step 3: The product of Step 2 (5.93 g, 0.021 mol) and1-tert-butoxy-carbonyl-3S-methyl piperazine (4.2 g, 0.021 mol) weredissolved in anhydrous CH₃CN (20 ml) and oven-dry K₂CO₃ (4.35 g, 0.032mol) was added to the solution. The mixture was stirred under reflux for2 days, then diluted with water. EtOAc extractive work up followed bysilica gel chromatography gave the desired product (3.16 g) in 39%yield.

Step 4: TFA (10 ml) was added to a solution of the product of Step3(1.15 g, 2.59 mmol) in CH₂Cl₂ (5 ml) and the mixture was stirred at RTfor 2 h, then concentrated under reduced pressure. NaOH (3N) was addedto the residue and extractive work up with EtOAc gave the desired aminein quantitative yield.

Step 5: The product of Step 4 and 1-tert-butoxycarbonyl-4-piperidone(0.94 g, 4.74 mmol) were treated with Ti(OiPr)₄, Et₂AlCN and CH₃MgBr ina manner similar to that described in Example 8, step 1, to obtain thedesired product (1.09 g) in 87% yield (from the amine of Step 4).

Step 6: TFA (4 ml) was added to a solution of the product of Step 5(0.76 mg, 1.57 mmol) in CH₂Cl₂ (2 ml) and the mixture was stirred at RTfor 2 h before it was concentrated under reduced pressure. NaOH (3N) wasadded to the residue and extractive work up with EtOAc gave the desiredamine in quantitative yield.

Step 7: The amine of Step 6 and 4,6-dimethylpyrimidine 5-carboxylic acid(0.36 g, 2.35 mmol), were coupled as described in Example 8, Step 4, toobtain the title compound (0.58 g) in 72% yield. M.p. 160; HRMS (MH⁺)found: 518.3123.

Using a similar procedure, compounds of the formula

were prepared wherein Z, R³, R⁶ and R² are as defined in the tablebelow: Ex. Z R³ R⁶ R² Dec.(0° C.) HRMS 27A N Me H

185 491.2744 27B N Me H

190 506.2729 27C N Me Me

190 505.2898 27D N Me Me

200 520.2902 27E OH Et Me

197 533.3097 27F OH Et Me

215 532.3147 27G OH Et Me

230 627.3145 27H OH Et Me

210 602.3678 27I OH Et Me

215 531.3305 27J OH Et Me

215 593.3470 27K OH Et Me

195 609.3424 27L OH Et Me

170 745.2308 27M N n-Pr Me

204 533.3207 27N N n-Pr Me

210 617.3798 27O N n-Pr Me

202 531.3304 27P N n-Pr Me

165 543.3311 27Q N n-Pr Me

225 584.3205 27R N n-Pr Me

195 548.3217

Using similar procedures, the following compounds were also prepared:

EXAMPLE 28

Steps 1-4:

Step 1: The cyano amine was prepared from p-trifluoromethyl benzaldehydeand 2(S)-methyl-4-(tert-butoxycarbonyl) piperazine exactly as describedin Example 6, Step 1.Step 2: A solution of the cyano amine 2 (2.5 g; 6.53 mmol) in 30 ml ofdry THF was placed under a blanket of N₂ and cooled to −78° C. Thissolution was treated with a solution of sodium hexa-methyl disilazide inTHF (1M; 26 ml) followed after 5 min with neat allyl bromide (6 ml).Upon removal of the bath and letting the reaction mixture warm to RT (˜1h), it changed from a yellow solution to dark reddish brown solution.The reaction was quenched with saturated NH₄Cl solution and the productextracted with EtOAc, washed with water, brine and dried. Concentrationin vacuo afforded a brown semi solid. FSGC of this material using 25%Et₂O in hexane as eluant gave 2.5 grams (92%) of the desired product asan amber gum (TLC R_(f)=0.65, 0.6 for two overlapping spots).Step 3: A solution of the product of Step 2 (2.4 g) in CH₃OH was treatedwith 10% Pd/C (0.2 g) and placed under a balloon of H₂ gas. Afterstirring at RT for 4 h, the catalyst was removed via filtration throughcelite. Concentration of the filtrate yielded an amber gum.

The α-propyl nitrile obtained above was dissolved in CH₃CN (12 ml).Magnesium bromide etherate (2.1 g; 8.14 mmol) and sodium triacetoxyborohydride (3.44 g; 16.2 mmol) were added and the reaction mixture wasstirred at RT overnight. The reaction was quenched with water andrendered basic with saturated NaHCO₃. The organic products wereextracted with EtOAc and processed to obtain ˜2 g of crude material.FSGC (10-25% Et₂O in hexane) served to isolate two diasteromericproducts (1.7 g total; 79% for two steps):

(S, S)-Diastereomer (A): TLC R_(f)=0.6 (25% Et₂O-Hexane). 0.9 g of acolorless gum.

(R, S)-Diastereomer (B): TLC R_(f)=0.5 (25% Et₂O-Hexane). 0.8 g of acolorless gum.

Step 4: Removal of the BOC-protecting group from the intermediate A wasaccomplished by treatment with TFA in CH₂Cl₂. The isolated freepiperazine (0.68 g; 2.3 mmol), N-(tert-butoxycarbonyl)-4-piperidinone(0.45 g; 2.3 mmol) and Ti(OiPr)₄ (0.7 mL; 2.5 mmol) were dissolved in 10ml of CH₂Cl₂ and stirred overnight. Et₂AlCN (1M in toluene; 2.7 ml) wasintroduced into the reaction mixture and the resultant solution wasstirred for a day. The reaction was diluted with EtOAc and quenched withwater. Celite was added to aid in the filtration of titanium andaluminum salts. The biphasic filtrate was washed with water, brine anddried. Concentration in vacuo yielded 1.1 g of a yellow gum (TLCR_(f)=0.55 in 25% EtOAc-hexane).

The resultant ipso-cyano compound was dissolved in dry THF (8 ml) andtreated with a solution of CH₃MgBr (3M in Et₂O; 6 ml) and stirredovernight at RT. The reaction flask was placed in a cold water bath andcarefully quenched with saturated NH₄Cl solution. The organic productwas extracted with EtOAc and washed with water and brine. Concentrationto a crude product which was purified by rapid FSGC (10-25% EtOAc inhexane) gave the BOC-piperidinyl compound as a pale yellow gum (1.1 g;100%). TLC R_(f)=0.6 in 25% EtOAc-hexane.Step 5: The BOC-protecting group on the piperidine nitrogen in theproduct of Step 4 was removed by treatment with TFA in CH₂Cl₂.Basification with 1 M NaOH and processing in CH₂Cl₂ afforded theunprotected piperidine in 90% yield. This intermediate was coupled(EDCI, HOBt) to aryl and heteroaryl carboxylic acids to obtain theamides exemplified in the following table:

wherein R² is as defined in the table: Ex. R² Mp (° C.) HRMS (MH⁺) 28A

249 Calculated: 532.3263 Found: 532.3268 28B

59 Calculated: 547.3260 Found: 547.3278 28C

246 Calculated: 530.3358 Found: 530.3372 28D

239 Calculated: 542.3358 Found: 542.3361 28E

258 Calculated: 583.3260 Found: 583.3272 28F

102 Calculated: 623.3573 Found: 623.3572 28G

216 Calculated: 545.3467 Found: 545.3459 28H

217 Calculated: 546.3307 Found: 546.3309 28I

223 Calculated: 616.3838 Found: 616.3848

Using similar procedures, the following compounds were prepared:

wherein R⁸, R³ and R² are as defined in the table: Ex. R⁸ R³ R² Mp (°C.) 28J —CF₃

195-220 28K —CF₃

105-115 28L CH₃CONH—

177-180 28M —CF₃

224-232

Using 3-fluoro benzyl bromide or chloride in place of benzyl bromide inthe procedure of Example 28, steps 1-4 (processing isomer B in step 3),then using the process of Example 1, step 5, followed by the process ofExample 26, steps 6-7, the following compound was prepared (HCl salt):

EXAMPLE 29

Steps 1-3:

Step 1: Solid m-CPBA was added to a solution of p-trifluoromethylstyrene (3 g; 17.4 mmol) in 30 ml of CH₂Cl₂ and stirred at RT for 20 h.About 20 ml of a saturated solution of NaHCO₃ was added and stirred atRT for 2 h. The mixture was diluted with 20 ml of CH₂Cl₂ and the organicproduct extracted into the CH₂Cl₂ layer. The organic extract wasprocessed to obtain the crude product. FSGC gave 3 g (90%) of thedesired epoxide as a colorless oil. TLC R_(f)=0.8 (25% EtOAc in hexane).Step 2: Freshly prepared NaOCH₃ (0.6 g; 10.6 mmol) was added to asolution of the product of Step 1 (2 g; 10.6 mmol) in 20 ml of anhydrousCH₃OH. After stirring at RT for a day, CH₃OH was removed in vacuo. Theresidue was dissolved in CH₂Cl₂ and washed with water and brine.Concentration, followed by FSGC, furnished 1.3 g (55%) of the carbinolas a colorless oil (R_(f)=0.3 50% Et₂O in hexane).Step 3: The carbinol of Step 2 (1.3 g; 5.9 mmol) was dissolved in CH₂Cl₂and cooled in an ice bath. Sequential treatment with Et₃N (1.7 ml; 12mmol) and CH₃SO₂Cl (0.6 ml; 7.7 mmol) and stirring for 30 min formed themesylate. The product was extracted by standard work up (yield=100%).

The mesylate (1.76 g; 5.9 mmol) and 2(S)-methyl-4-(tert-butoxycarbonyl)piperazine (2.4 g; 12 mmol) were dissolved in 5 ml of CH₃CN and heatedto reflux for 19 h. The reaction mixture was cooled to RT and directlysubjected to flash chromatography on silica gel. Eluting with 25%, then50% Et₂O in hexane served to isolate the diastereomeric products A and B(Total yield=86%). A: R_(f)=0.5 (50% Et₂O in hexane). Light yellow gum(0.9 g; 42%) B: R_(f)=0.4 (50% Et₂O in hexane). Amber gum (1.13 g; 44%)

Step 4: Reductive amination of the free piperazine dervied from A (0.9g; 2.2 mmol) with N-BOC-piperidin-4-one with the installation of theipso-methyl group was carried out as described in Example 1, step 4, toobtain the BOC-protected piperidinyl compound (0.87 g; 92%). R_(f)=0.3(50% EtOAc in hexane).Step 5: The BOC protecting group was removed from the piperidinenitrogen via TFA, and the resultant compound was coupled with acidsusing the EDCI/HOBt method as described in Example 8, step 4, to obtainthe compounds shown in the following table:

wherein R² is as shown in the table: Ex. R² Mp (° C.) HRMS (MH⁺) 29A

163 Calculated: 534.3056 Found: 534.3050 29B

208 Calculated: 548.3100 Found: 548.3092 29C

101 Calculated: 549.3053 Found: 549.3057 29D

192 Calculated: 618.3631 Found: 618.3638

EXAMPLE 29E

The piperidine A (130 mg), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (130 mg), 1-hydroxybenzotriazole (92 mg), anddiisopropylethylamine (0.3 mL) were taken up in CH₂Cl₂ and stirred at25° C. for 19 h. The solution was diluted with CH₂Cl₂ and washed with 1N NaOH (aq.). The aqueous layer was extracted with CH₂Cl₂ and dried overMgSO₄. Filtration and concentration gave a yellow oil. Purification viapreparative thin-layer chromatography (10/1 acetone/hexanes, SiO₂) gave95 mg (51%) of compound 29E as a colorless oil. HRMS calcd (MH⁺):550.3005; Found: 550.3000.

A was prepared according to Steps 1-5 for Example 29 set forth above.

The pyrimidine acid was prepared according to the procedure outlined forExample 23C Steps 1 and 2 set forth above.

Compound 29E can also be isolated as the metabolite of compound 29A inplasma, urine, bile or fecal sample of a patient who has beenadministered compound 29A as set forth below in Example 29F. In additionto compound 29E, other compounds that can be isolated as metabolites inhuman or other animal species include the following:

EXAMPLE 29F Isolation of Metabolites

Chemicals: ¹⁴C-Vicriviroc[1-[(4,6-dimethyl-5-pyrimidinyl)carbonyl]-4-[4-[2-methoxy-1(R)-[4-(trifluoromethyl)phenyl]ethyl]-3(S)-methyl-1-piperazinyl]-4-methylpiperidine,i.e., ¹⁴C-compound 29A shown below]

was synthesized at Schering-Plough Research Institute (Kenilworth, N.J.)and had >97% radiochemical purity. All other compounds/referencestandards were obtained from the Department of Chemical Research atSchering-Plough Research Institute. HPLC grade acetonitrile and methanolwere from Burdick and Jackson (Muskegon, Mich.). Water was purifiedusing the Millipore Milli-Q_(plus) water purification system (Bedford,Mass.).

Test Species: Weight or Body Mass Species Age Index (BMI) Oral DoseHuman (M) 8-50 yr BMI = 19-29 50 mg ¹⁴C-compoud (n = 8) kg/m² 29Amaleate (100 μCi) in water Monkey (M & F) 2-5 yrs 2-5 kg 5 mg/kg (25.8μCi/mg) (n = 4) ¹⁴C-compound (Strain: 29LA in water Cynomolgus macaque)Rat (M & F) 7-10 wk 175-270 g 6 mg/kg (12.3 μCi/mg) (n = 3) ¹⁴C-compound29A (Strain: in 0.4% methylcellulose Sprague Dawley)M = Male;F = Female;n = number of animals/subjects per genderSample Collection: Urine and feces over selected intervals and blood atselected time points were collected from healthy male volunteers,monkeys and rats through 336-hr, 432-hr and 168-hr post dose,respectively.Radioactivity: Total radioactivity was measured using liquidscintillation spectrometer (LSS).Sample Processing for Profiling and Characterization of Metabolites:Sample Pooling:

For each species, plasma samples were pooled across subjects/animals bytime point. All the other matrices were first pooled for a desiredcollection interval within each subject/animal and then acrosssubjects/animals to obtain a composite sample containing>90% of theradioactivity excreted in each respective matrix. Species Plasma (hr)Urine (hr) Feces (hr) Human Pre-dose^(a), 4, 8 & 24 0-96 0-264 MonkeyPre-dose, 1 & 4 0-168 0-72 Rat Pre-dose, 2, 8, 12 & 24 0-48 (M) & 0-720-72 (F)^(a)Pre-dose plasma was used for optimizing extractionprocedure/conditionsM = Male and F = Female

Sample Processing: Matrix Methods Plasma SPE using Oasis HLB cartridges(Waters Corp., Milford, MA) or Solvent extraction with proteinprecipitation using acetonitrile Urine SPE using Oasis HLB cartridges(Waters Corp., Milford, MA) or direct Injection Feces Solvent extractionusing methanolMobile Phase and HPLC Conditions:

HPLC column was maintained at room temperature for all LC-MS andLC-MS^(n) experiments. The mobile phase, which consisted of 95% 10-mMammonium acetate (pH 6.0) containing 5% acetonitrile (A) and 95%acetonitrile and 5% water (B), was maintained at a constant flow rate (1mL/min). For all LC-MS experiments, the column effluent was split todivert 20-25% into TSQ Quantum (ThermoElectron, San Jose, Calif.) massspectrometer and the balance into a Flow Scintillation Analyzer (FSA)analyzer.

Mobile Phase Gradient:

Separation of metabolites was achieved using programmed linear changesin mobile phase composition as summarized in the following table: Time(min) % A % B 0.0 90 10 10.0 70 30 40.0 30 70 40.1 10 90 50.0 10 90 50.190 10 60.0 90 10

HPLC and FSA System: Equipment Model and Vendor HPLC Pump, Controller,Alliance Model 2690 (Waters Corp., Degasser, Column Oven Milford, MA)and Autosampler Flow Scintillation Model 500TR (Packard Instrument Co.,Analyzer (FSA) Meriden, CT) Flow Scintillation 250 or 500 μL (PackardInstrument Analyzer Cell Volume Co., Meriden, CT) Scintillation FluidUltima Flo M at 2.4 mL/min (Packard Instrument Co., Meriden, CT) ColumnLuna Phenyl-Hexyl 250 × 4.6 mm, 5-μm particle size (Phenomenex,Torrance, CA). Guard Column MetaGuard Polaris C18-A, 5-μm particle size(Metachem Technologies, Torrance, CA).Mass Spectrometer:

All LC-MS and LC-MS/MS experiments were performed using a TSQ massspectrometer (ThermoElectron, San Jose, Calif.) nominally operated underthe conditions listed below: Parameter Setting Ionization SourceElectrospray Ionization (ESI) Ionization Mode Positive Spray NeedleVoltage 4.0-4.5 kV Capillary Temperature 250-270° C. Sample Flow rate0.20-0.25 mL/min after splitting Sheath Gas Nitrogen (25-50) AuxiliaryGas Nitrogen (4-15)

Radiochromatograms from study samples were examined to locateradioactive peaks corresponding to metabolites. After correcting for thedelay time (0.2-0.5 min), each radiolabelled peak was examined forpossible molecular ions related to the drug and/or its putativemetabolites. Based on the elution order, metabolite peak labels wereassigned as M1 to M48 where M48 is the first eluting compound and M1 isthe last to elute from the column. (see FIGS. 1-3 below). Whenavailable, synthetic reference standards were used to confirm thestructural assignment.

Results

As shown in Table 1, following 50 mg single oral administration of VICto healthy male volunteers, the dose was near equally eliminated inurine and feces. By contrast, a majority (53-71%) of the dose wasrecovered in the feces from all non-clinical species investigated. Asshown in FIG. 1, VIC was rapidly and extensively metabolized in human,monkey and rat after a single 50 mg, 6-mg/kg, and 5-mg/kg oraladministration of ¹⁴C-VIC, respectively. Since there were no sex-relatedqualitative differences in the metabolism of VIC, only the profiles foreach matrix from male rats and monkeys are shown in FIGS. 2-4. TABLE 1Excretion of radioactivity as % of dose in humans (50 mg dose), monkeys(5 mg/kg dose) and rats (6 mg/kg dose) following a single oraladministration of ¹⁴C-Vicriviroc. Human (n = 8) Monkey (n = 4) Rat (n =3) Urine Feces Urine Feces Urine Feces Time (h) M M M F M F M F M FTotal^(b) 47.1 45.1 26.3 25.8 48.6 56.4 18.0 15.6 69.1 72.9^(a)Number of animals^(b)Urine and fecal samples were collected for 0-336, 0-432 and 0-168 hrfrom humans, monkeys and rats respectively.FIG. 1 shows the biotransformation of Vicriviroc in Human, Monkey andRat following a single oral dose of ¹⁴C-VIC.FIG. 2 shows a comparison of representative radiochromatographicProfiles of Pooled Plasma Extract Following a Single Oral Administrationof Vicriviroc to Healthy Male Volunteers, Male Monkeys and Rats.

The following table describes the distribution of compound 29A(vicriviroc) and its metabolites in plasma in human, monkey and ratspecies. VIC and Metabolites (Plasma) Species Major Minor Trace HumanVicriviroc VIC-N-Oxide (M2/M3). M4 (m/z 550), M7 (VIC) O-desmethyl-VIC(m/z 538), M10 (m/z (M15), O- 508), M14 (m/z 550), desmethyl-VIC- M16(m/z 494), glucuronide (M35), M18/M19 (m/z 536), monooxy-O- M20/M20a(m/z 534), desmethyl-VIC- M21/M22 (m/z 536), glucuronide (M37) M25 (m/z520), & N-desalkyl-VIC M25e/M25f/M25g (m/z (M41) 649), M30/M31 (m/z536), M35b/M37a (534) & M36 (m/z 712) Monkey Vicriviroc VIC-N-Oxide(M2/M3). M1 (m/z 400), M4 (VIC) VIC-hydroxylamine (m/z 550), M6 (m/z(M7) O-desmethyl- 518), M16 (m/z 494), VIC (M15), O- M18/M19 (m/z 536),desmethyl-VIC- M21/M22 (m/z 536), glucuronide (M35), M25 (m/z 520),VIC-hydroxylamine- M25e/M25f/M25g (m/z glucuronide (M26), 649), M28 (m/zO-desmethyl-VIC- 480) & M36 (m/z 712) glucuronide (M35), VIC-carboxylicacid (M35b/M37a), monooxy-O- desmethyl-VIC- glucuronide (M37),N-desalkyl-VIC (M41) & monooxy- N-desalkyl-VIC (M45/M46/M47) VIC-N-OxideM10 (m/z 508), M14 (M2/M3). monooxy- (m/z 550), VIC (M4), Rat VicrivirocO-desmethyl-VIC M16 (m/z 494), (VIC) (M15), O- M18/M19 (m/z 536),desmethyl-VIC M20/M20a (m/z 534), (M25), N-desalkyl- M22 (m/z 536), M27VIC (M41) & (m/z 536), M30/M31 monooxy-N- (m/z 536), M35 (m/zdesalkyl-VIC 696) & M36/M37 (m/z (M45/M46/M47) 712)Major: Components with ≧20% of the total chromatographic radioactivity(TCR);Minor: Components between 3 and 20% of the TCR;Trace: Components with <3% of the TCR and/or only detected with a massspectrometerBased on the above, the following observations can be made:

-   -   Qualitatively similar profiles were observed in plasma from        human, monkey and rat.    -   The major circulating drug derived component in human, monkey        and rat was VIC.    -   While glucuronide conjugate of O-desmethyl-VIC (M35) was a        prominent circulating metabolite in human and monkey plasma, in        rats this metabolite was only detected in trace quantities.    -   There was no human specific circulating metabolite detected.        FIG. 3 shows a Comparison of Representative Radiochromatographic        Profiles of Pooled Urine Following a Single Oral Administration        of Vicriviroc to Healthy Male Volunteers, Male Monkeys and Rats.

The following table describes the distribution of compound 29A(vicriviroc) and its metabolites in urine of human, monkey and ratspecies. VIC and Metabolites (Urine) species Major Minor Trace HumanO-desmethyl- VIC, VIC-N- M1 (m/z 400), M4 VIC- Oxide (M2/M3). (m/z 550),M7 (m/z glucuronide O-desmethyl- 538), M10 (m/z (M35) & N- VIC (M15),508), M14 (m/z 550), desalkyl- monooxy-O- M16 (m/z 494), VIC (M41)desmethyl- M18/M19 (m/z 536), VIC (M18/ M19a/M19b (m/z M19), M20/ 534),M21/M22 (m/z M20a (m/z 536), M22a/M22b 534), monooxy- (m/z 550), M25O-desmethyl- (m/z 520), VIC- M25e/M25f/M25g glucuronide (m/z 649), M28(M37) & monooxy- (480), M34a/M34b/ N-desalkyl- M34c (m/z 712), VIC(M45/M46/ M30/M31 (m/z 536), M47) M35b/M37a (534) & M36 (m/z 712) MonkeyO-desmethyl- VIC, VIC-N- M1 (m/z 400), M4 VIC- Oxide (M2/M3), (m/z 550),M6 (m/z glucuronide VIC- 518), M10 (m/z (M35), N- hydroxylamine 508),M15 (m/z desalkyl- (M7), monooxy- 536), M16 (m/z VIC (M41) O-desmethyl-494), M23 (m/z & monooxy- VIC (M18/M19), 494), M25 (m/z N-desalkyl-M20/M20a (m/z 520), M25e/M25f/ VIC (M45/ 534), monooxy- M25g (m/z 649),M46/M47) O-desmethyl- M28 (480) & M36 VIC (M21/M22), (m/z 712) VIC-hydroxylamine- glucuronide (M26) & monooxy-O- desmethyl-VIC- glucuronide(M37) Rat N-desalkyl- VIC, VIC-N- M1 (m/z 400), M4 VIC (M41) Oxide(M2/M3), (m/z 550), M6 (m/z O-desmethyl- 518), M10 (m/z VIC (M15), 508),M20/M20a N,N-desalkyl- (m/z 534) & VIC (M16), M35b/M37a (m/z monooxy-O-534) desmethyl- VIC (M18/M19), monooxy-O- desmethyl- VIC (M21/ M22), O-desmethyl- VIC (M25), N,N-dealkyl- O-desmethyl- VIC (M28), O- desmethyl-VIC-glucuronide (M35) & monooxy- N-desalkyl-VIC (M45/M46/M47)Major: Components with ≧3% of the administered dose.Minor: Components between 0.5 and 3% of the administered dose.Trace: Components with <0.5% of the administered dose and/or onlydetected with a mass spectrometerBased on the above, the following observations can be made:

-   -   Major urinary metabolites N-desalkyl-VIC (M41) and        O-desmethyl-VIC-glucuronide (M35) collectively accounted for        21%, 8% and 4% of the dose in human, monkey and rat,        respectively.    -   While M35 contributed to 11% and 3% of the dose in urine, this        metabolite accounted for less than 1% in the urine from rat.        FIG. 4 shows a comparison of representative radiochromatographic        profiles of pooled fecal extract following a single oral        administration of Vicriviroc to healthy male volunteers, male        monkeys and rats.

The following table describes the distribution of compound 29A(vicriviroc) and its metabolites in feces of human, monkey and ratspecies. VIC and Metabolites (Feces) Species Major Minor Trace HumanN-desalkyl- VIC, Monooxy-VIC M6 (m/z 518), M7 VIC (M41) & (M14).O-desmethyl- (m/z 538), M10 (m/z M20/M20a VIC (M15), N,N- 508), M14 (m/z(m/z 534) desalkyl-VIC 550), M19a/M19b (M16), N,N- (m/z 534), M23desalkyl-VIC (m/z 494), M25 (M16a), monooxy- (m/z 520), M27 (m/zO-desmethyl- 536) & M28 (480) VIC (M19), M25e/M25f/M25g (m/z 649),VIC-carboxylic acid (M35b/ M37a) & monooxy- N-desalkyl-VIC (M45/M46/M47)Monkey N-desalkyl- VIC, VIC- M1 (m/z 400), M6 VIC (M41) & hydroxylamine(m/z 518), M10 M20/M20a (M7), N,N- (m/z 508), M15 (m/z 534) desalkyl-VIC(m/z 520), M16 (M16a), N,N- (m/z 494) & M18/ desalkyl-VIC M19 (m/z 536)& (M23), monooxy- M21/M22 (m/z 536) VIC (M22a), M25e/M25f?M25g (m/z649), N,N- desalkyl-O- desmethyl-VIC (M28), monooxy- VIC (M33), VIC-carboxylic acid (M35b/M37a) & monooxy-N- desalkyl-VIC (M45/M46/M47) RatN-desalkyl- VIC, monooxy- M1 (m/z 400), VIC (M41) & VIC (M4), VIC- M2/M3(m/z 550), O-desmethyl- hydroxylamine M5a/M5b (m/z VIC (M15) (M7), N,N-548), M6 (m/z desalkyl-VIC 518), M10 (m/z (M16), monooxy- 508), M20/M20aO-desmethyl- (m/z 534) & M25d VIC (M19), O- (m/z 536) desmethyl-VIC(M25), M25e/ M25f/M25g (m/z 649), N,N- desalkyl-O- desmethyl-VIC (M28),M35a1 (m/z 600), VIC- carboxylic acid (M35b/M37a) & monooxy-N-desalkyl-VIC (M45/M46/M47)Major: Components with ≧5% of the administered dose.Minor: Components between 1 and 5% of the administered dose.Trace: Components with <1% of the administered dose and/or only detectedwith a mass spectrometer

Based on the above, the following observation can be made:

-   -   Major fecal metabolites which collectively accounted for 16-35%        of the administered dose in human, monkey and rat included        N-desalkyl-VIC (M41), O-demethyl-VIC(M15) and a oxidative        product of M15 (M20/M20a at m/z of 534).        The overall conclusion from the metabolite studies are as        follows:    -   Following a single oral 50 mg administration to healthy        volunteers, Vicriviroc (VIC, compound 29A) and its metabolites        were near equally excreted in feces and urine. By contrast,        following a single 5 mg/kg and 6 mg/kg oral administration of        VIC to rats and monkeys, respectively, radioactivity was        predominantly eliminated in the feces.    -   In all species investigated, the primary biotransformation of        VIC involved O-demethylation, N-dealkylation, oxidation and        glucuronidation.    -   No human specific metabolites were observed following a single        50 mg oral administration of VIC to healthy male volunteers.

EXAMPLE 30

Step 1:

A solution of p-trifluoromethoxy benzaldehyde (0.48 ml, 3.36 mmol), thepiperidino-pipiperazine (1.00 g, 3.36 mmol) and benzotriazole (0.48 g,4.00 mmol) in dry toluene were heated at reflux for 6 h. The reactionmixture was cooled to RT and the solvent was removed in vacuo. FollowingNMR verification of the formation of the product, the product was usedwithout further purification in the next step.Step 2:

To a solution of the product of Step 1 (1.16 g, 1.97 mmol) in 20 ml oftoluene was added a solution of n-propyl magnesium bromide (2M in Et₂O,1.1 ml) and the mixture stirred at RT for 15 h. The reaction mixture wasquenched by pouring onto ice and saturated aqueous NH₄Cl solution. Theaqueous layer was extracted with EtOAc, washed with 1M NaOH solution,water and brine. Concentration and purification by FSGC (20%EtOAc-hexane) provided the desired product A. Further elution with 30%EtOAc in hexane gave the (R, S) diastereomer B.

Step 3: The amine A was treated with TFA in CH₂Cl₂ to remove theBOC-protecting group. Coupling of the free piperidine with acids usingEDCI/HOBt provided compounds 30-30B in the following table; similarmethods were used to prepare compounds 30C-I.

HRMS (MH⁺) Ex. R^(8a) R³ R² MP (° C.) found 30 —OCF₃ n-Pr

237 546.3314 30A —OCF₃ n-Pr

241 548.3217 30B —OCF₃ n-Pr

219 632.3779 30C H

175-178 — 30D H

177-189 — 30E H

84-90 — 30F —CF₃

180-192 — 30G* —CF₃

180-186 — 30H H

178-188 — 30I* —OCF₃

165-175 —*Mixture of diastereomers

EXAMPLE 31

A solution of the product of Example 12, step 2 (150 mg, 0.27 mmol),imidazole (27.4 mg, 0.403 mmol), 1,10-phenanthroline (48 mg, 0.27 mmol),trans,trans-dibenzylideneacetone (6.28 mg, 0.027 mmol), copper (II)trifluoromethanesulfonate benzene complex (15 mg, 0.027 mmol) and Cs₂CO₃(96.1 mg, 0.30 mmol) in xylene (2 ml) was stirred at 110° C. for 5 days.The reaction mixture was cooled to RT and saturated NaHCO₃ was added.Extractive EtOAc work up followed by silica gel chromatography gave thetitle compound (70 mg, 52% yield). Dec. 215° C. (HCl salt).

HRMS calcd for C₂₉H₃₉ClN₃OS (M+H+) 500.3389, found 500.3396.

The following assays can be used to determine the CCR5 antagonisticactivity of the compounds of the invention.

CCR5 Membrane Binding Assay:

A high throughput screen utilizing a CCR5 membrane binding assayidentifies inhibitors of RANTES binding. This assay utilizes membranesprepared from NIH 3T3 cells expressing the human CCR5 chemokine receptorwhich have the ability to bind to RANTES, a natural ligand for thereceptor. Using a 96-well plate format, membrane preparations areincubated with ¹²⁵I-RANTES in the presence or absence of compound forone hour. Compounds are serially diluted over a wide range of 0.001ug/ml to 1 ug/ml and tested in triplicates. Reaction cocktails areharvested through glass fiber filters, and washed thoroughly. Totalcounts for replicates are averaged and data reported as theconcentration required to inhibit 50 percent of total ¹²⁵I-RANTESbinding. Compounds with potent activity in the membrane binding assayare further characterized in secondary cell-based HIV-1 entry andreplication assays.

HIV-1 Entry Assay:

Replication defective HIV-1 reporter virions are generated bycotransfection of a plasmid encoding the NL4-3 strain of HIV-1 (whichhas been modified by mutation of the envelope gene and introduction of aluciferase reporter plasmid) along with a plasmid encoding one ofseveral HIV-1 envelope genes as described by Connor et al, Virology, 206(1995), p. 935-944. Following transfection of the two plasmids bycalcium phosphate precipitation, the viral supernatants are harvested onday 3 and a functional viral titer determined. These stocks are thenused to infect U87 cells stably expressing CD4 and the chemokinereceptor CCR5 which have been preincubated with or without testcompound. Infections are carried out for 2 hours at 37° C., the cellswashed and media replaced with fresh media containing compound. Thecells are incubated for 3 days, lysed and luciferase activitydetermined. Results are reported as the concentration of compoundrequired to inhibit 50% of the luciferase activity in the controlcultures.

HIV-1 Replication Assay:

This assay uses primary peripheral blood mononuclear cells or the stableU87-CCR5 cell line to determine the effect of anti-CCR5 compounds toblock infection of primary HIV-1 strains. The primary lymphocytes arepurified from normal healthy donors and stimulated in vitro with PHA andIL-2 three days prior to infection. Using a 96-well plate format, cellsare pretreated with drug for 1 hour at 37° C. and subsequently infectedwith an M-tropic HIV-1 isolates. Following infection, the cells arewashed to remove residual inoculum and cultured in the presence ofcompound for 4 days. Culture supernatants are harvested and viralreplication measured by determination of viral p24 antigenconcentration.

Calcium Flux Assay:

Cells expressing the HIV coreceptor CCR5 are loaded with calciumsensitive dyes prior to addition of compound or the natural CCR5 ligand.Compounds with agonist properties will induce a calcium flux signal inthe cell, while CCR5 antagonists are identified as compounds which donot induce signaling by themselves but are capable of blocking signalingby the natural ligand RANTES.

GTPγS Binding Assay:

A GTPγS binding assay measures receptor activation by CCR5 ligands. Thisassay measures the binding of ³⁵S labeled-GTP to receptor coupledG-proteins that occurs as a result of receptor activation by anappropriate ligand. In this assay, the CCR5 ligand, RANTES, is incubatedwith membranes from CCR5 expressing cells and binding to the receptoractivation (or binding) is determined by assaying for bound ³⁵S label.The assay quantitatively determines if compounds exhibit agonistcharacteristics by inducing activation of the receptor or alternativelyantagonist properties by measuring inhibition of RANTES binding in acompetitive or non-competitive fashion.

Chemotaxis Assay:

The chemotaxis assay is a functional assay which characterizes theagonist vs. antagonist properties of the test compounds. The assaymeasures the ability of a non-adherent murine cell line expressing humanCCR5 (BaF-550) to migrate across a membrane in response to either testcompounds or natural ligands (i.e., RANTES, MIP-1β). Cells migrateacross the permeable membrane towards compounds with agonist activity.Compounds that are antagonists not only fail to induce chemotaxis, butare also capable of inhibiting cell migration in response to known CCR5ligands.

The role of CC chemokine receptors such as CCR-5 receptors ininflammatory conditions has been reported in such publications asImmunology Letters, 57, (1997), 117-120 (arthritis); Clinical &Experimental Rheumatology, 17 (4) (1999), p. 419-425 (rheumatoidarthritis); Clinical & Experimental Immunology, 117 (2) (1999), p.237-243 (atopic dermatitis); International Journal ofImmunopharmacology, 20 (11) (1998), p. 661-7 (psoriasis); Journal ofAllergy & Clinical Immunology, 100 (6, Pt 2) (1997), p. S52-5 (asthma);and Journal of Immunology, 159 (6) (1997), p. 2962-72 (allergies).

In the assay to determine inhibition of RANTES binding, compounds of theinvention range in activity from a Ki of about 0.5 to about 1500 nM,with preferred compounds having a range of activity from about 0.5 toabout 750 nM, more preferably about 0.5 to 300 nM, and most preferablyabout 0.5 to 50 nM. The results for preferred and representativecompounds of formulas I and II in the test to determine inhibition ofRANTES binding are given in the table below. In the table, “Ex. No.”stands for “Example Number” and “nM” stands for “nanomolar.” Ki (nM)Inhibition of Ex. No. RANTES binding 3C 9.97 6C 30.0 6E 1.43 11 10.5 1660 20A 1300 23 2.95

For preparing pharmaceutical compositions of the CCR5 antagonistcompounds described by this invention, inert, pharmaceuticallyacceptable carriers can be either solid or liquid. Solid formpreparations include powders, tablets, dispersible granules, capsules,cachets and suppositories. The powders and tablets may be comprised offrom about 5 to about 95 percent active ingredient. Suitable solidcarriers are known in the art, e.g. magnesium carbonate, magnesiumstearate, talc, sugar or lactose. Tablets, powders, cachets and capsulescan be used as solid dosage forms suitable for oral administration.Examples of pharmaceutically acceptable carriers and methods ofmanufacture for various compositions may be found in A. Gennaro (ed.),Remington's Pharmaceutical Sciences, 18th Edition, (1990), MackPublishing Co., Easton, Pa.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection or addition of sweeteners and opacifiers fororal solutions, suspensions and emulsions. Liquid form preparations mayalso include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g. nitrogen.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The CCR5 antagonist compounds of the invention may also be deliverabletransdermally. The transdermal compositions can take the form of creams,lotions, aerosols and/or emulsions and can be included in a transdermalpatch of the matrix or reservoir type as are conventional in the art forthis purpose.

Preferably the CCR5 antagonist compound is administered orally.

Preferably, the pharmaceutical preparation is in a unit dosage form. Insuch form, the preparation is subdivided into suitably sized unit dosescontaining appropriate quantities of the active component, e.g., aneffective amount to achieve the desired purpose.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from about 10 mg to about 500 mg, preferably fromabout 25 mg to about 300 mg, more preferably from about 50 mg to about250 mg, and most preferably from about 55 mg to about 200 mg, accordingto the particular application.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage regimen for a particular situation iswithin the skill of the art. For convenience, the total daily dosage maybe divided and administered in portions during the day as required.

The amount and frequency of administration of the CCR5 antagonistcompounds of the invention and/or the pharmaceutically acceptable saltsthereof will be regulated according to the judgment of the attendingclinician considering such factors as age, condition and size of thepatient as well as severity of the symptoms being treated. A typicalrecommended daily dosage regimen for oral administration can range fromabout 100 mg/day to about 300 mg/day, preferably 150 mg/day to 250mg/day, more preferably about 200 mg/day, in two to four divided doses.

The doses and dosage regimen of the NRTIs, NNRTIs, PIs and other agentswill be determined by attending clinician in view of the approved dosesand dosage regimen in the package insert or as set forth in the protocoltaking into consideration the age, sex and condition of the patient andthe severity of the HIV-1 infection.

While the present invention has been described in conjunction with thespecific embodiments set forth above, many alternatives, modificationsand variations thereof will be apparent to those of ordinary skill inthe art. All such alternatives, modifications and variations areintended to fall within the spirit and scope of the present invention.

1. A compound in pure and isolated form, said compound being selectedfrom the group consisting of

or a pharmaceutically acceptable salt, solvate or ester thereof.
 2. Thecompound of claim 1, wherein said compound is

or a pharmaceutically acceptable salt or solvate thereof.
 3. Thecompound of claim 1, wherein said compound is

or a pharmaceutically acceptable salt, solvate, or ester thereof.
 4. Thecompound of claim 1, wherein said compound is

or a pharmaceutically acceptable salt, solvate or ester thereof.
 5. Thecompound of claim 1, wherein said compound is

or a pharmaceutically acceptable salt, solvate, or ester thereof.
 6. Thecompound of claim 1, wherein said compound is

or a pharmaceutically acceptable salt or solvate thereof.
 7. Apharmaceutical composition comprising an effective amount of a compoundof claim 1 or a pharmaceutically acceptable salt, solvate or esterthereof in combination with a pharmaceutically acceptable carrier.
 8. Amethod of treating Human Immunodeficiency Virus comprising administeringto a human in need of such treatment a therapeutically effective amountof the compound of claim 1 or a pharmaceutically acceptable salt,solvate or ester thereof.
 9. The method of claim 8 further comprisingadministering one or more antiviral or other agents useful in thetreatment of Human Immuno-deficiency Virus in combination with thecompound of claim 1 or a pharmaceutically acceptable salt, solvate orester thereof.
 10. The method of claim 9 wherein the antiviral agent isselected from the group consisting of nucleoside reverse transcriptaseinhibitors, non-nucleoside reverse transcriptase inhibitors and proteaseinhibitors.
 11. The method of claim 10 wherein the antiviral agent isselected from the group consisting of zidovudine, lamivudine,zalcitabine, didanosine, stavudine, abacavir, adefovir dipivoxil,Iobucavir, BCH-10652, emitricitabine, beta-L-FD4, DAPD, Iodenosine,nevirapine, delaviridine, efavirenz, PNU-142721, AG-1549, MKC-442,(+)-calanolide A and B, saquinavir, indinavir, ritonavir, nelfinavir,lasinavir, DMP-450, BMS-2322623, ABT-378, amprenavir, hydroxyurea,ribavirin, IL-2, IL-12, pentafuside, Yissum No. 11607 and AG-1549.
 12. Amethod treating solid organ transplant rejection, graft v. host disease,arthritis, rheumatoid arthritis, inflammatory bowel disease, atopicdermatitis, psoriasis, asthma, allergies or multiple sclerosis,comprising administering to a human in need of such treatment atherapeutically effective amount of the compound of claim 1 or apharmaceutically acceptable salt, solvate or ester thereof.
 13. Themethod of claim 12 for the treatment of solid organ transplantrejection, graft v. host disease, arthritis, rheumatoid arthritis,inflammatory bowel disease, atopic dermatitis, psoriasis, asthma,allergies or multiple sclerosis, further comprising one or more otheragents useful in the treatment of said diseases.
 14. A kit comprising inseparate containers in a single package pharmaceutical compositions foruse in combination to treat Human Immunodeficiency Virus which comprisesin one container a pharmaceutical composition comprising an effectiveamount of the compound of claim 1 or a pharmaceutically acceptable salt,solvate or ester thereof in a pharmaceutically acceptable carrier, andin separate containers, one or more pharmaceutical compositioncomprising an effective amount of a antiviral or other agent useful inthe treatment of Human Immunodeficiency Virus in a pharmaceuticallyacceptable carrier.
 15. A method of determining if a patient has beenadministered the compound of the formula

the method comprising the step of determining if a plasma, urine, bileor fecal sample obtained from the patient shows the presence of acompound of claim 1.